Review Article C9ORF72 hexanucleotide repeats in behavioral and motor neuron disease: clinical heterogeneity and pathological diversity
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
Am J Neurodegener Dis 2014;3(1):1-18
www.AJND.us /ISSN:2165-591X/AJND1402003
Review Article
C9ORF72 hexanucleotide repeats in behavioral and
motor neuron disease: clinical heterogeneity
and pathological diversity
Jennifer S Yokoyama1, Daniel W Sirkis2, Bruce L Miller1
1
Department of Neurology, University of California, San Francisco, CA, USA; 2Department of Molecular and Cell
Biology and Howard Hughes Medical Institute, University of California at Berkeley, Berkeley, CA, USA
Received February 10, 2014; Accepted March 10, 2014; Epub April 2, 2014; Published April 12, 2014
Abstract: Hexanucleotide repeat expansion in C9ORF72 is the most common genetic cause of frontotemporal de-
mentia (FTD), a predominantly behavioral disease, and amyotrophic lateral sclerosis (ALS), a disease of motor
neurons. The primary objectives of this review are to highlight the clinical heterogeneity associated with C9ORF72
pathogenic expansion and identify potential molecular mechanisms underlying selective vulnerability of distinct
neural populations. The proposed mechanisms by which C9ORF72 expansion causes behavioral and motor neuron
disease highlight the emerging role of impaired RNA and protein homeostasis in a spectrum of neurodegeneration
and strengthen the biological connection between FTD and ALS.
Keywords: C9ORF72, frontotemporal dementia, amyotrophic lateral sclerosis, motor neuron disease, RNA, protein
trafficking
Introduction tical atrophy in all lobes of the brain, with cere-
bellar and thalamic atrophy emerging as distin-
A GGGGCC hexanucleotide repeat expansion guishing features of C9+ when compared to
intronic to chromosome 9 open reading frame sporadic disease in FTD/FTD-MND (reviewed in
72 (C9ORF72) was identified in 2011 [1, 2] as [9]) and ALS [10, 11]. One notable observation
the most common genetic cause of amyo- has been the diversity of phenotype associated
trophic lateral sclerosis (ALS, or Lou Gehrig’s with C9+ patients [12], which will be highlighted
disease) and frontotemporal dementia (FTD) below. The clinical heterogeneity associated
with or without concomitant motor neuron dis- with C9ORF72 expansion is predicted to be a
ease (MND). The literature on C9ORF72 has reflection of the well-established structural and
expanded greatly in the ensuing two years, pathological heterogeneity [13]. Identifying the
leading to characterization of the frequency of molecular mechanisms responsible for the
pathogenic expansion carriers (C9+) in diverse apparent morphological and pathological diver-
populations and to putative molecular mecha- sity will be critical for making predictions about
nisms underlying the pathogenicity of such clinical outcomes in carriers of this shared
expansions. genetic risk factor.
In addition to two forms of TDP-43 pathology Clinical features of C9ORF72 expansion-medi-
(harmonized [3] Type A and B), C9+ is also char- ated disease
acterized by Ub+/p62+/TDP-43- inclusions,
most notably in cerebellum, thalamus and hip- Motor features
pocampus; the latter pathology is unique to
C9+ and, in some cases, this may be the only Pathologic expansion of C9ORF72 is the most
form of pathology [4-8]. These pathological common genetic cause of ALS, estimated at
findings are broadly mirrored by neuroimaging around 34% of familial and 6% of sporadic ALS
findings describing diffuse cortical and subcor- cases [13]. C9+ ALS patients may demonstrateC9ORF72 in behavioral and motor disease
more bulbar onset of symptoms (reviewed in potential to affect multiple aspects of motor
[13, 14]). MND occurs concomitantly in about control, which could lead to less common motor
30% of C9+ FTD [13]. C9+ may be a rare cause syndromes.
of other motor neuron disorders as well. One
Behavioral features
study investigating a large Dutch cohort found
N=4 individuals with progressive muscular Behaviorally, C9ORF72 expansion is most com-
atrophy and N=1 patient with primary lateral monly associated with a clinical syndrome of
sclerosis with expanded repeats [15] highlight- behavioral variant (bv)FTD, characterized by
ing the variability of upper and/or lower motor deficits in social behavior and executive func-
neuron involvement associated with C9ORF72 tion. Less common diagnoses include primary
expansion. progressive aphasia (PPA), predominant
amnestic, and psychiatric clinical syndromes.
Some C9+ patients also show Parkinsonism, Some individuals also show deficits in visuo-
with or without MND. Parkinsonism symptom- spatial function (reviewed in [25]). In addition,
atology usually appears after onset of FTD or cognitive and behavioral impairments appear
ALS findings, and is likely explained by neurode- to be more common in ALS patients with C9+
generation of the substantia nigra in many C9+ versus sporadic ALS [11]. Some cases of bvFTD
cases [16]. Hexanucleotide expansion of associated with C9+ have remarkably slow pro-
C9ORF72 has also been associated with a gression and little to no visible neuroanatomi-
handful of cases with clinical diagnoses of idio- cal involvement [16, 26-28]. In addition to lack
pathic Parkinson’s disease (PD) [17-19]. of frank brain atrophy, self-awareness of dis-
Intermediate repeat length has also been sug- ease remains relatively intact, and patients are
gested as a risk factor for sporadic PD in two sometimes able to make behavioral modifica-
studies surveying large numbers of patients: tions to compensate for the deficits imparted
for >20-30+ repeats in N=889 Caucasian PD by disease [26]. This insight is in contrast to the
or essential tremor plus Parkinsonism patients, majority of bvFTD patients, where there is
and for ≥7 repeats in N=911 Han Chinese PD marked lack of awareness into social and emo-
patients [20, 21]. Further investigations in tional deficits [29].
diverse populations are required to confirm
In the context of these broader clinical syn-
these findings.
dromes, specific psychiatric symptoms may fur-
Isolated cases of progressive supranuclear ther differentiate C9+ patients from other
palsy, corticobasal, and olivopontocerebellar patients with sporadic or genetic forms of FTD.
degeneration syndromes have also been In particular, psychotic features may be
enriched in C9ORF72 expansion carriers, with
reported, further expanding the spectrum of
delusions and hallucinations more common in
phenotypes associated with C9+ [19, 22].
C9+ versus matched sporadic cases [30, 31].
Whether these rare cases are associated with
In one Swedish C9+ kindred, psychotic symp-
C9+ pathology specifically in the basal ganglia,
toms and somatic complaints were observed in
brainstem, and cerebellum remain to be
the majority of affected individuals [32]. Anxiety
determined. and depressive symptoms [8] are also observed
Regions expressing the C9ORF72 mouse ortho- in C9+. These symptoms may relate to findings
that C9ORF72 expansion is associated with
log (discussed in more detail in the next sec-
unique pathology in critical regions of the limbic
tion) include the striatum (a component of the
system such as the thalamus and hippocam-
basal ganglia), brainstem, and cerebellum [23].
pus [4-8]. Similarly, in Alzheimer’s disease (AD),
Neuroimaging and pathological studies show
degeneration of the hippocampus may allow
that the cerebellum, which plays a critical role
‘release’ of its regulation of the amygdala,
in motor control, is particularly affected in C9+
resulting in higher levels of anxiety and emo-
disease. The thalamus—which appears unique- tional contagion [33]. In addition, degeneration
ly involved in C9+ compared to sporadic dis- of the cerebellum could result in ‘disconnec-
ease—participates in both the direct and indi- tion’ of the emotion-regulating portions of this
rect pathways linking the striatum and motor brain region from the cortex [34].
cortex, resulting in motor stimulation and inhi-
bition, respectively [24]. Thus, pathological Occasionally, C9+ patients present clinically
changes in cerebellum and thalamus have the with an AD-like dementia; in a recent screen of
2 Am J Neurodegener Dis 2014;3(1):1-18C9ORF72 in behavioral and motor disease
FTD genes in early-onset AD patients, two indi- observed within the C9+ patient population
viduals were found to harbor C9ORF72 expan- could be a result of distinct pathogenic mecha-
sions [35]. In these cases, neuroimaging may nisms (or combinations thereof) occurring in
be particularly informative if findings are atypi- different individuals.
cal of AD but instead show frontotemporal
involvement [36]. Amnestic presentation may C9ORF72 haploinsufficiency
be related to the hippocampal sclerosis and/or
p62+ pathology observed in the hippocampus Loss of C9ORF72 protein function from reduced
of many C9+ patients [4-8]. In addition, episod- expression due to pathogenic expansion is one
ic memory deficits in C9+ correlate with atro- proposed mechanism of disease. The expand-
phy in the frontal, temporal and parietal corti- ed copy of C9ORF72 results in reduced gene
ces, including the posterior cingulate cortex, expression due to histone trimethylation, as
and are distinct from the regions correlated measured in blood [45, 46]. This gene is pre-
with episodic memory in sporadic bvFTD (i.e., dominantly expressed in neural populations
medial prefrontal, medial and lateral temporal vulnerable in FTD and ALS. Specifically, the
cortices) [37]. Finally, visuospatial deficits are mouse ortholog of C9ORF72 is expressed in
in line with observed parietal lobe involvement the hippocampus, dentate gyrus, striatum,
in C9+ (reviewed in [9]). This further highlights thalamus, brainstem nucleus, cerebellum,
how anatomic heterogeneity in C9ORF72 throughout the cortex, and in the spinal cord,
expansion-mediated disease may contribute to as well as several peripheral tissues. In mouse,
a diversity of clinical symptoms. The diversity of expression appears to be limited primarily to
clinical behavioral syndromes associated with gray matter [23]. Recent studies in both C. ele-
C9ORF72 expansion strongly suggests the gans and zebrafish indicate that loss of
presence of pathology in distinct areas of the C9ORF72 function may be associated with
brain across individuals. motor neuron degeneration [47, 48].
Molecular mechanisms of C9ORF72 disease The protein product of C9ORF72 is predicted to
be structurally similar to the Differentially
If C9ORF72 expansion is associated with Expressed in Normal and Neoplasia (DENN)
altered structural organization of the brain that family of guanine nucleotide exchange factors
culminates in a wide-spectrum of clinical dis- that activate Rab-GTPases (Rab-GEFs), which
ease, what molecular mechanisms might are important regulators of membrane traffic
explain these changes? The three primary mod- [49, 50]. The putative yeast ortholog of
els accounting for C9ORF72 expansion-mediat- C9ORF72, Lst4p, prevents lysosomal delivery
ed toxicity [38] are: (1) loss of C9ORF72 protein of cargo by redirecting endosome-localized pro-
function [1, 2]; (2) accumulation of toxic RNA teins to cell surface [51]. If C9ORF72 similarly
foci [39], which sequester RNA-binding proteins serves to sort endosomal cargo to the plasma
such as TDP-43, FUS, hnRNP A3 [40], and Pur membrane in neurons, then mutations reduc-
α [41] and result in dysregulation of RNA splic- ing its function would be predicted to augment
ing, trafficking and translation; (3) novel dipep- lysosomal degradation of particular cargo pro-
tide aggregate formation resulting from non- teins. Intriguingly, the membrane protein
ATG mediated (RAN) translation of the expanded TMEM106B, which has recently been shown to
GGGGCC hexanucleotide repeat [42, 43]. be a genetic modifier of both progranulin- and
Additional mechanisms that could modify dis- C9-mediated FTD, appears to influence both
ease pathogenesis include differential expan- lysosomal morphology and dendritic trafficking
sion size of C9ORF72 hexanucleotide repeats of lysosomes within neurons [52, 53]. In addi-
across different tissues and independent tion, homozygous loss-of-function mutations in
genetic modifiers that mediate any of the fac- progranulin result in neuronal ceroid lipofusci-
tors that lead to neuronal toxicity. Also of note, nosis, a lysosomal storage disorder [54].
recent evidence suggests that C9+ toxicity may Dysfunctional degradation within the endo-
not necessarily occur cell-autonomously in neu- lysosomal pathway may thus represent a com-
rons; any of the proposed mechanisms of toxic- mon molecular pathology associated with
ity may in fact occur first in astrocytes and sub- altered levels of C9ORF72, progranulin and
sequently spread to neurons [44]. Potentially, TMEM106B. Consistent with this scenario,
the large degree of clinical heterogeneity accumulation of ubiquitinated proteins down-
3 Am J Neurodegener Dis 2014;3(1):1-18C9ORF72 in behavioral and motor disease
stream of impaired lysosomal degradation most abundant in neurons of the frontal cortex,
could explain the Ub+/p62+/TDP-43- patholo- and to a lesser extent in astrocytes, microglia
gy that discriminates C9+ from other forms of and oligodendrocytes [62]. Accumulation of
FTD and ALS. expanded RNA into toxic foci is a disease mech-
anism implicated in other neurodegenerative
van der Zee and colleagues found decreased expansion disorders such as several spinocer-
expression of C9ORF72 with an increased ebellar ataxias and fragile-X associated with
number of repeats at intermediate repeat num- tremor/ataxia syndrome (FXTAS) [1]. Screening
bers [55]. rGGGGCC (but not rCCCCGG) repeats for point mutations in C9ORF72 via sequencing
form stable, tract length- and RNA concentra- of 389 ALS samples did not render any patho-
tion-dependent unimolecular and multimolecu- genic variants, further suggesting that C9ORF-
lar RNA G-quadruplexes [56, 57], which can 72 pathogenesis is caused by a toxic gain of
affect promoter activity, genetic instability, RNA function due to RNA foci resulting from the non-
splicing, translation and mRNA localization coding expansion [63]. These RNA foci have the
within neurites. The dose-dependence of sta- potential to sequester other RNA-binding pro-
bility of these structures suggests a mecha- teins, which could result in widespread effects
nism by which increased repeat length would on transcriptional regulation and protein
be more toxic. These RNA structures are poten- expression.
tially amenable to intervention with small mol-
ecules that break up G-quadruplexes [58-60]. One RNA-binding protein critically linked to C9+
This repeat (and how it folds) may serve as a disease is TDP-43. As one of the main protein
mechanism by which splice variation occurs aggregates found in C9+ FTD/ALS, TDP-43 is a
(given redistribution of C9ORF72 splice vari- DNA- and RNA-binding protein that cycles
ants with expansion); ASF/SF2 splicing factor between the nucleus and cytosol (though it
can bind to this repeat [57]. localizes primarily to the nucleus) and plays
numerous roles in RNA metabolism, including
One patient has been reported with a homozy- transcription and regulation of splicing, trans-
gous repeat expansion; this individual had an port and translation, miRNA processing, and
early onset of bvFTD but typical clinical and stress granule formation (reviewed in [38]).
pathological presentation within the spectrum Mutations in TARDBP, which encodes TDP-43,
of C9+ heterozygous disease. The authors of cause ALS (reviewed in [64]). TDP-43 binds and
this report suggest that this case provides evi- regulates hundreds of RNA targets, including
dence that haploinsufficiency is not the only an enrichment of genes involved in neuronal
mechanism of C9+ disease as one would development and synaptic function [65, 66].
expect a more severe or different clinical phe- TDP-43 is critical for early embryonic develop-
notype associated with homozygous loss of ment of the central nervous system [67, 68]
C9ORF72 expression compared to heterozy- and plays an important role in the association
gous loss [61]. Toxic gain of function would be and size of stress granules, which form tran-
in line with an earlier onset but phenotypically siently in response to cellular stress (e.g., [69];
similar form of C9+ disease, though it is also reviewed in [38, 70, 71]). This suggests a pos-
possible that presence of genetic or environ- sible mechanism by which early sequestration
mental disease modifiers play a role in this of TDP-43 could cause alterations in multiple
individual. proteins involved in neuronal development and
function that could ultimately result in altered
Sequestration of RNA-binding proteins into structural and/or network architecture that is
RNA foci vulnerable to diffuse cortical and subcortical
damage. This would then be exacerbated by
Another potential mechanism of toxicity alterations in the cellular stress response due
involves the GGGGCC expansion itself, whereby to altered stress granule dynamics.
toxic RNA foci are formed that sequester RNA-
binding proteins and splicing factors such as Identification of specific RNA-binding proteins
TDP-43 and FUS, the latter of which was identi- that bind the C9ORF72 GGGGCC repeat expan-
fied in rGGGGCC binding screen [40]. Both sion is currently underway. In a recent screen,
sense and antisense RNA foci have been identi- Xu, et al. found that rGGGGCC binds the RNA-
fied via in situ hybridization, where they are binding protein Pur α, and overexpression of
4 Am J Neurodegener Dis 2014;3(1):1-18C9ORF72 in behavioral and motor disease
Pur α rescues rGGGGCC-mediated neurode- expression changes—that is, reducing RNA foci
generation in Drosophila [41]. Pur α is involved formation—may prove beneficial for C9+ carri-
in modulation of gene transcription, transla- ers with distinct clinical presentations. In sup-
tion, controls cell cycle and differentiation and port of this notion, antisense oligonucleotides
is a component of RNA-transport granules [72, (ASOs) targeting the C9ORF72 transcript sup-
73]. The putative disease mechanism would pressed RNA foci formation and reversed gene
thus be a loss of function of Pur α due to bind- expression changes and aberrant cell excitabil-
ing to rGGGGCC. Of note, Pur α also binds the ity associated with the pathologic expansion
FXTAS GCC repeat [74]. This model of neurode- [81, 82] suggesting a potential therapeutic
generation in Drosophila would thus argue intervention.
against a primary role for loss of C9ORF72
function in disease pathogenesis. RAN-dependent translation of GGGGCC expan-
sions
Another screen for rGGGGCC RNA-binding pro-
teins identified hnRNP A3, which forms p62+/ Repeat-associated non-ATG (RAN)-dependent
TDP-43- neuronal cytoplasmic and intranuclear translation of dipeptides from both sense and
inclusions in hippocampus, as well as cerebel- anti-sense strands of the expanded hexanucle-
lum in a subset of C9+ [40]. hnRNP A3 cycles otide repeat in C9ORF72 form insoluble aggre-
between the nucleus and cytoplasm and is gates [42, 43, 83]. RAN translation of the sense
involved in alternative pre-mRNA splicing, strand creates poly Gly-Arg (poly-GR), poly Gly-
nuclear import and cytoplasmic trafficking of Pro (poly-GP), and poly Gly-Ala (poly-GA) dipep-
mRNA, as well as mRNA stability, turnover and tides which are hydrophobic and aggregation-
translation [75]. Expressed primarily in the prone; anti-sense RAN translation results in
nucleus of neurons, it appears to be redistrib- Pro-Ala, Pro-Gly, and Pro-Arg dipeptides. Using
uted to cytosol in its pathological state, simi- an antibody binding the poly-GP dipeptides,
larly to TDP-43 and FUS [76-79]. The hnRNP A3 Ash, et al. showed variability in pathological
finding was not replicated by Xu, et al. but this location [42]. Highest presence included hippo-
discrepancy could relate to differences in bind- campal regions, motor cortex, temporal and
ing conditions and protein concentrations [41]. frontal cortices, amygdala, anterior and lateral
Also of note, a screen in Drosophila for FXTAS- thalamus, and Purkinje cells of the cerebellum.
repeat associated changes in miRNA expres- RAN-translated dipeptides have been shown to
sion identified miRNA-277; hnRNP A2/B1 can colocalize with p62+ inclusions [42, 43] in
directly regulate miRNA-277, which modulates granule cells of the cerebellum, cells in the den-
CGG repeat-mediated neurodegeneration in tate gyrus, and the CA4 of the hippocampus
FXTAS [80]. In iPSCs derived from C9+ ALS [84].
patients, repeat-containing RNA foci colocal-
ized with hnRNPA1 and Pur α [81]. The presence of inclusion bodies of these
dipeptides does not appear to correlate with
The ability of RNA foci to sequester RNA-binding clinical severity or neurodegeneration (whereas
proteins and thus alter the processing and TDP-43 pathology does), and has been sug-
expression of hundreds of distinct genes in a gested by some to be a protective response to
stochastic nature [38, 39] could result in mark- coping with large numbers of dipeptides rather
edly diverse forms of disease across different than a driving force of neurodegenerative pro-
individuals. With known genetic modifiers cesses [85]. This evidence, however, does not
(TMEM106B, described in more detail below) preclude the possibility that soluble forms of
and variability in the number of hexanucleotide the dipeptides, or variation in the distribution of
repeats it is not surprising that C9ORF72 the different types of dipeptides across brain
expansion results in a diverse set of anatomi- tissue, could contribute to the clinical and/or
cal, clinical and pathologic phenotypes. Utilizing pathological manifestations of C9+ disease.
large datasets to identify patterns of RNA
expression change across multiple C9+ indi- Formation of RAN-translated dipeptides can
viduals with the same clinical syndrome may be also be partially ameliorated with ASOs in
useful for dissecting the spectrum of changes mouse models [86] and iPSC-differentiated
that are most likely to predict a particular set of neurons [82], however, ASO intervention in C9+
symptomatology. Targeting the cause of the iPSCs appears to ameliorate gene expression
5 Am J Neurodegener Dis 2014;3(1):1-18C9ORF72 in behavioral and motor disease
and cellular deficits despite continued pres- expansion correlated with older age of onset
ence of RAN translated dipeptides [82], further [90]. However, other studies showed that
suggesting that RAN-translated products may expansion length varies across tissues (e.g.,
be a secondary or downstream mechanism blood versus brain [88, 89]) suggesting mea-
which has less influence on pathology. sures from periphery may not be representa-
Additional testing of this type of intervention in tive of expansion size in the brain [13]. Another
the context of clinical disease may help to study found that C9ORF72 expansion length
determine the role that RAN-translated dipep- did not correlate with FTD, FTD-MND or MND
tides play in C9ORF72 expansion-mediated diagnostic groups in frontal cortex, cerebellum
disease. or blood samples; they found that longer frontal
cortex expansion length correlated with older
Notably, the amount of RAN translation that age of onset in FTD only, and that longer cere-
occurs could alter the availability of rGGGGCC bellar expansion length was associated with
repeats to sequester RNA-binding proteins, reduced survival [88]. A third study did not find
since RAN translation would be expected to correlations between C9+ length in cerebellum
reduce the binding of proteins such as TDP-43 and age of onset or disease duration, but found
and Pur α. Thus it is possible that the amount that cerebellar expansion length was higher in
of RNA-binding protein sequestration versus ALS versus FTD [89]. Thus, it remains unclear
RAN-mediated translation that occurs in each what role expansion length in different brain
cell is variable, offering yet another source of regions plays in C9+ disease.
disease heterogeneity. If indeed dipeptide
aggregates are not toxic to the cell [82, 85], Finally, evidence suggests that intermediate
then it stands to reason that formation of repeat expansion lengths that fall under the
dipeptides through RAN-mediated translation “pathologic” cutoff of 30 repeats but are above
may be an adaptive mechanism by which the what is considered normal (less than 20) may
cell attempts to limit the formation of RNA foci serve as a risk factor for sporadic FTD [91], ALS
and sequestration of RNA-binding proteins. In [92], and PD [20, 21]. This is in line with evi-
line with this theory, Gendron, et al. found that dence suggesting that intermediate repeat
RAN-translated poly-GP peptides infrequently lengths are associated with reduced C9ORF72
colocalized with RNA foci [83]. For neurons with expression, if protein haploinsufficiency plays a
long axons, such as motor neurons, alterations role in C9+ pathogenesis. Further work will be
in RNA-binding proteins may be particularly required to characterize the role of expansion
problematic (e.g., myotonic dystrophy) [87]. length in pathological and clinical hetero-
Thus, the balance of RAN translation versus geneity.
RNA foci formation in particular neuronal sub-
types could potentially affect disease patho- Genetic modifiers of C9ORF72 expansion dis-
genesis and thus clinical presentation. ease: It is likely that genetic variation plays a
role in modifying the pathological and clinical
Other variables that may play a role in C9+ manifestation of C9+ disease. Mutations in
disease other ALS-associated genes have now been
found in C9+ carriers suggesting a two-hit
Expansion-size differences across tissue: The model of disease (e.g., [93-96]), in line with the
C9ORF72 hexanucleotide repeat expansion oligogenic theory of ALS, which suggests that
length is highly variable and likely unstable due harboring multiple risk variants in different
to surrounding genomic architecture ([55]; ALS-associated genes is sufficient to cause dis-
reviewed in [14]). C9 expansion size varies ease (reviewed in [97-99]). C9+ patients that
across different brain regions [88-90] and also carried deleterious variation in other FTD
between monozygotic twins [89], and larger genes (GRN or MAPT) demonstrated early dis-
expansions may contribute to more potent ease onset, bvFTD clinical presentation, and no
pathology in the affected network of neurons. motor neuron involvement suggesting a paral-
Three studies have investigated this with vary- lel two-hit model for FTD [100].
ing results. One study of blood samples found
that C9+ length did not correlate with diagnos- Common variation in other neurodegenerative
tic group when comparing FTD, ALS, and other disease associated genes may also contribute
neurodegenerative phenotypes, but longer to clinical heterogeneity in C9+ carriers. This
6 Am J Neurodegener Dis 2014;3(1):1-18C9ORF72 in behavioral and motor disease
relationship has been observed in patients with face, such that they do not reach the lysosome.
GRN mutations, where carrying the AD risk If this function is conserved in humans, reduced
allele APOE-ε4 resulted in exacerbated disease C9ORF72 levels might be associated with
progression, amnestic syndromes and accom- defects in the endo-lysosomal pathway. In addi-
panying amyloid pathology [101]. For example, tion, TMEM106B, the genetic modifier of both
pathologic C9ORF72 expansion coupled with a progranulin- and C9 expansion-associated FTD,
high-risk genetic polymorphism in an ALS gene has recently been implicated in lysosomal traf-
could represent a risk mechanism predisposing ficking in neurons [52, 53]. In particular,
some C9+ individuals to MND, whereas indi- TMEM106B appears to negatively regulate ret-
viduals without these additional risk variants rograde transport of lysosomes within den-
may have a predominantly behavioral form of drites, with reductions in TMEM106B associat-
disease. This remains an untested hypothesis ed with movement of lysosomes toward the
worth exploring in the context of disease-modi- neuronal soma [52]. Since TMEM106B influ-
fying risk genes. ences lysosome function and modulates pro-
granulin levels [52, 107], it is tempting to spec-
In addition to exacerbating clinical presenta- ulate that its protective role in C9+ carriers
tion, genetic variation also has the potential to might similarly involve the endo-lysosomal
reduce disease risk. A recent study by van pathway, providing a common link to two genet-
Blitterswijk, et al. identified variation in TMEM- ic forms of FTD. Finally, the finding that some
106B, which was previously associated with C9+ carriers harbor unique Ub+/p62+/TDP-43-
protection from FTD with TDP-43 pathology pathology further implicates dysfunctional
(FTD-TDP) [102, 103] as protective in C9+ autophagy, as p62 is a ubiquitin-binding pro-
patients with FTD but not MND [104]. One study tein which accumulates when autophagy is
also found that variation in TMEM106B protect- impaired [108]. Since lysosomal degradation is
ed against cognitive change in ALS patients the ultimate endpoint of autophagy, defects in
[105]. Taken together, these results suggest lysosomal trafficking or degradation would be
that TMEM106B may broadly modify behavior- expected to produce the observed Ub+/p62+/
al/cognitive symptoms associated with TDP-43 TDP-43- pathology that is seen in C9+ carriers.
pathology and may thus represent a robust A mutation in the multivesicular body protein
therapeutic target [106]. CHMP2B leading to familial FTD in a Danish
pedigree further implicates dysregulation of
C9ORF72 expansion as a disease of dysfunc-
the endo-lysosomal system as a pathological
tional cellular trafficking
mechanism leading to FTD [109, 110].
Recent studies in model organisms C. elegans C9ORF72 pathogenesis spreads through neu-
and zebrafish provide compelling evidence that roanatomical networks
loss of C9ORF72 function is pathogenic to
motor neurons [47, 48] and leads to motor defi- The underlying pattern of neurodegeneration in
cits. While it is currently unclear if loss of C9+ may be the best starting point for under-
C9ORF72 function contributes to disease in standing how one type of genetic variant can
C9+ carriers, the observation that C9ORF72 result in such heterogeneous clinical presenta-
transcript levels are reduced in patients with tions. The pattern of diffuse gray and white
FTD and FTD-MND suggests that loss of pro- matter involvement observed in C9+ FTD/FTD-
tein function should be seriously considered as MND (reviewed in [9]) and ALS [10, 11] patients
a disease mechanism. stands in contrast to the idea of neurodegen-
erative processes spreading through specific,
What cellular consequences might be expected clearly defined functional brain networks [111,
due to loss of C9ORF72 function? Sophisticated 112]. Two intriguing hypotheses suggest how
homology searches have revealed that these patterns may fit into the ‘selective vulner-
C9ORF72 is a full-length homolog of the DENN ability’ framework: 1) the epicenter of vulnera-
family of Rab-GEFs, as noted above [49, 50]. bility in C9+ neurodegeneration is highly and
While nothing is known about the cell biological diffusely interconnected to both cortical and
function of mammalian C9ORF72, its yeast subcortical regions of the brain; 2) functional
ortholog has been implicated in the sorting of brain networks in C9ORF72 expansion carriers
endosome-localized proteins to the cell sur- are less strongly defined (i.e., there is more
7 Am J Neurodegener Dis 2014;3(1):1-18C9ORF72 in behavioral and motor disease
inter-network connectivity than intra-network characterization, and may benefit from studies
connectivity). of resting state connectivity seeded within spe-
cific thalamic nuclei and studies of thalamic
The first theory proposes a ‘central station’ microstructural connectivity [117, 118].
node that serves as a major hub for multiple
different pathways throughout the brain such In contrast to the central node hypothesis, the
that degeneration of that network would result second theory suggests that the diffuse pat-
in a diffuse pattern of cortical atrophy and pro- tern of neurodegeneration observed in C9+
found white matter integrity loss. One such patients may be a by-product of damage that is
centrally connected subcortical structure is the spreading throughout multiple functional net-
thalamus. Divided into numerous functionally works rather than being isolated in a single,
distinct nuclei, the thalamus receives sensory defined functional circuit, and implicates early
and motor information from a variety of corti- systemic disorganization as the underlying
cal, cerebellar, and brainstem efferent projec- cause of diffuse non-selective spread. Reduced
tions, and then relays it through afferent projec- network connectivity has been observed even
tions to the cortex for further processing and prior to symptom onset in Huntington’s disease
integration. Each nucleus has specific afferent (HD), another neurodegenerative disorder
and efferent projections associated with it, and caused by DNA repeat expansion in the HTT
the nuclei themselves are also highly connect- gene. Pathogenic HTT expansion carriers show
ed (reviewed in [113]). One longitudinal study of lower cortico-striatal functional connectivity as
C9+ patients found neuroimaging patterns con- compared to controls, even prior to disease
sistent with spread through such a distributed onset [119]. Early changes in brain organiza-
subcortical network, with thalamic and cerebel- tion have been suggested in a transgenic rat
lar atrophy most prominent while cortical atro- model of HD [120], with differential aging pat-
phy appeared diffuse and nonspecific [114]. terns observed in the brains of transgenic rats
as compared to wildtype as early as the first
Given the behavioral component of FTD, the year of life [121]. Microstructure alterations in
dorsomedial nucleus is one tempting candidate brain regions relevant to HD were also seen in
given its interconnectivity with the prefrontal, these transgenic rats during postnatal develop-
cingulate, and association cortices, and its ment [122], though further study is required to
involvement could also contribute to memory determine if similar changes occur in people.
deficits observed in a subset of C9+ carriers
[115, 116]. Also, the pulvinar nucleus domi- Identifying early changes in brain structure and
nates the posterior portion of the thalamus and function in C9ORF72-expansion carriers may
is highly interconnected with the occipital cor- help to disentangle these two hypotheses,
tex, as well as adjacent areas of the parietal which are not necessarily mutually exclusive.
For example, a highly connected node of C9+
and temporal cortices. These two nuclei, along
neurodegeneration could be identified during
with the lateral posterior—which receives affer-
prodromic stages of disease, with longitudinal
ent projects from occipital cortex and projects
follow-up demonstrating insidious spread
to the parietal cortex—make up the ‘associa-
across multiple, interconnected functional net-
tive’ functional group of thalamic nuclei involved
works of the brain. On the other hand, early ani-
in high level cognition [34]. The ventral anterior
mal experiments established that retrograde
and ventral lateral nuclei receive inputs from
degeneration of thalamic nuclei occurs when
basal ganglia and cerebellum, and project to
damage is inflicted upon the cortical area that
premotor and motor areas of the frontal cortex,
specific nucleus projects to [123], suggesting a
respectively, and along with the ventral poste-
mechanism by which widespread cortical loss
rior nucleus compose the ‘effector’ group
across multiple networks could result in tha-
involved with movement and aspects of lan-
lamic neurodegeneration.
guage [34]. Functionally and anatomically,
these two groups of thalamic nuclei represent Contributions of C9ORF72 expansion to clini-
domains affected in the clinical syndromes cal heterogeneity
associated with C9ORF72 expansion thus far:
bvFTD, ALS/MND and PPA. The role of the thal- In addition to the phenotypic heterogeneity
amus in C9+ disease remains to be elucidated highlighted in preceding sections, C9+ disease
through careful pathological dissection and is also associated with other aspects of pheno-
8 Am J Neurodegener Dis 2014;3(1):1-18C9ORF72 in behavioral and motor disease
typic variability. As suggested by slowly pro- into a full clinical syndrome. Studies of sporadic
gressive C9+ bvFTD cases, there is a large bvFTD suggest that patients often have psychi-
variation in the length of disease course; some atric diagnoses years before referral to the neu-
groups have suggested that C9+ patients dem- rology clinic [130]. Whether these are simply
onstrate longer disease courses than matched misdiagnoses of an underlying neurodegenera-
sporadic cases (e.g., [124]) whereas others tive process or are, in fact, early manifestations
have observed shorter durations of disease of FTD remain to be determined.
(reviewed in [13]). Age of onset is also highly
variable, ranging from the 20’s – 80’s [13], with If C9+ pathogenesis begins in the thalamus,
50% penetrance by age 58 and nearly full pen- then the molecular mechanism of spread
etrance by age 80 [125]. One report, however, through the interconnected networks of the
described two C9+ carriers with no cognitive thalamic nuclei could involve physical spread of
impairments as of ages 80 and 84, suggesting toxic TDP-43 pathology in a seeded fashion
that C9ORF72 expansion has incomplete pen- [131], or functional spread whereby changes in
etrance [126]. Whether slowly progressive synaptic activity in the thalamus could result in
forms of C9+ bvFTD and predominant psychiat- downstream neuronal dysfunction. In mouse,
ric presentations are a result of reduced expan- C9ORF72 is robustly expressed in the thala-
sion size or other genetic or environmental mus [23], and unique Ub+/p62+/TDP-43-
modifiers remains to be established. pathology is often found in the thalamus of C9+
carriers, supporting a mechanism whereby
In sporadic neurodegenerative disease, there molecular changes resulting from C9ORF72
appears to be a sudden precipitous drop in cog- expansion could begin in this central subcorti-
nitive function several years before a full clini- cal region and then, over time, affect other
cal symptom manifests [127, 128]. However, in regions of the brain through its interconnected-
a genetically mediated adult-onset disease it is ness with cerebellar and diffuse cortical
difficult to deny the neurodevelopmental aspect structures.
– how is the brain of a disease-causing gene
carrier different from that of a non-carrier? Regardless of the mechanism, the fundamen-
Does the brain learn to ‘adapt’ to deficits, and tal leap to identifying effective biomarkers for
only during the aging process—which weakens making predictions of clinical prognosis and
neural plasticity—does dysfunction become disease progression will require linking periph-
apparent? Is there slow, insidious accumula- eral measures of disease with local pathologi-
tion of pathology in the neurons such that, only cal processes. This may include tracking chang-
after 50+ years, it comes to the point where es in the expression of C9ORF72 transcripts or
neurons are being killed? Or are there subtle other genes dysregulated (directly or indirectly)
signs that there is underlying dysfunction from by hexanucleotide-generated RNA foci and/or
the outset, but these go unrecognized until the RAN-translated dipeptides. Multimodal neuro-
symptoms become impossible to ignore? imaging may also serve as a sensitive measure
of C9-specific changes in gray and white matter
Whether a prodrome of neurodegenerative dis- structures over time [114, 132], even in pres-
ease exists remains unanswered; gene carriers ymptomatic carriers.
may provide a unique opportunity to study dis-
ease in its earliest stages, prior to frank symp- Concluding remarks
tom onset. For example, early personality/
behavioral changes have been described in In summary, C9ORF72-mediated disease is
some C9+ carriers [129]. In C9+ bvFTD characterized by heterogeneous clinical pre-
patients, there is often emotional dysregulation sentations of motor and/or behavioral syn-
reminiscent of cerebellar disconnection syn- dromes of ALS, bvFTD, or FTD-MND, as well as
drome [8, 34]. If subtle alterations in emotional less common diagnoses of PPA, primary
and/or physiological regulation reflect progres- amnestic presentation and psychiatric disease
sive neural dysfunction from a central node or such as depression or bipolar disorder.
due to systemic disorganization as proposed Parkinsonism is also a common symptom
above, then measures of these features could accompanying these clinical diagnoses. Three
provide a quantitative measure of these under- main molecular mechanisms of C9+ disease
lying pathological processes as they progress have emerged as potential contributors to this
9 Am J Neurodegener Dis 2014;3(1):1-18C9ORF72 in behavioral and motor disease
observed clinical heterogeneity: haploinsuffi- CA 94158, USA. Tel: 415-476-5565; Fax: 415-476-
ciency resulting in a loss of C9ORF72 protein 1816; E-mail: jyokoyama@memory.ucsf.edu
function, formation of RNA foci resulting in a
toxic gain of function, and formation of dipep- References
tide aggregates resulting from RAN-mediated
[1] DeJesus-Hernandez M, Mackenzie IR, Boeve
sense and antisense translation of the hexa-
BF, Boxer AL, Baker M, Rutherford NJ, Nichol-
nucleotide expansion. Variable expansion son AM, Finch NA, Flynn H, Adamson J, Kouri
length across tissue types and brain regions as N, Wojtas A, Sengdy P, Hsiung GYR, Karydas A,
well as contributions of other genetic modifiers Seeley WW, Josephs KA, Coppola G, Ge-
may provide additional sources of disease het- schwind DH, Wszolek ZK, Feldman H, Knop-
erogeneity. In addition, C9+ diseases may be man DS, Petersen RC, Miller BL, Dickson DW,
associated with alterations in cellular traffick- Boylan KB, Graff-Radford NR and Rademakers
ing, particularly within the endo-lysosomal R. Expanded GGGGCC hexanucleotide repeat
pathway. The mode of spread of one or more of in noncoding region of C9ORF72 causes chro-
these contributing pathological mechanisms mosome 9p-linked FTD and ALS. Neuron
could occur via a centrally located neural hub 2011; 72: 245-256.
[2] Renton AE, Majounie E, Waite A, Simón-Sán-
connecting multiple selectively vulnerable func-
chez J, Rollinson S, Gibbs JR, Schymick JC,
tional networks, or through multiple, intercon- Laaksovirta H, van Swieten JC, Myllykangas L,
nected networks converging on a common neu- Kalimo H, Paetau A, Abramzon Y, Remes AM,
roanatomical region. The diversity of clinico- Kaganovich A, Scholz SW, Duckworth J, Ding J,
pathology demonstrated by C9+ patients sug- Harmer DW, Hernandez DG, Johnson JO, Mok
gests a spectrum of disease manifestations K, Ryten M, Trabzuni D, Guerreiro RJ, Orrell
that ultimately culminate in unique protein RW, Neal J, Murray A, Pearson J, Jansen IE,
pathology (Ub+/p62+/TDP-43- in the cerebel- Sondervan D, Seelaar H, Blake D, Young K,
lum and hippocampus) and neuroanatomical Halliwell N, Callister JB, Toulson G, Richardson
damage (thalamic atrophy). A, Gerhard A, Snowden J, Mann D, Neary D,
Nalls MA, Peuralinna T, Jansson L, Isoviita VM,
Elucidation of novel genetic and molecular Kaivorinne AL, Hölttä-Vuori M, Ikonen E, Sul-
modifiers of C9-mediated disease progression kava R, Benatar M, Wuu J, Chiò A, Restagno G,
Borghero G, Sabatelli M, Consortium I, Hecker-
will provide the opportunity for development of
man D, Rogaeva E, Zinman L, Rothstein JD,
therapeutic interventions. In addition, identifi- Sendtner M, Drepper C, Eichler EE, Alkan C,
cation of biomarkers that predict future clinical Abdullaev Z, Pack SD, Dutra A, Pak E, Hardy J,
syndrome will be critical for identification of Singleton A, Williams NM, Heutink P, Pickering-
candidates for clinical trials. Finally, gaining a Brown S, Morris HR, Tienari PJ and Traynor BJ.
better understanding of the preclinical mani- A hexanucleotide repeat expansion in
festations of disease – whether they are behav- C9ORF72 is the cause of chromosome 9p21-
ioral, functional or physiological—will also pro- linked ALS-FTD. Neuron 2011; 72: 257-268.
vide deeper insight into the workings of the [3] Mackenzie IRA, Neumann M, Baborie A, Sam-
neuroanatomical system most vulnerable to pathu DM, Du Plessis D, Jaros E, Perry RH, Tro-
C9ORF72 expansion disease. janowski JQ, Mann DMA and Lee VMY. A har-
monized classification system for FTLD-TDP
Acknowledgements pathology. Acta Neuropathologica 2011; 122:
111-113.
[4] Al-Sarraj S, King A, Troakes C, Smith B, Maeka-
This work was supported by the Larry L. Hillblom
wa S, Bodi I, Rogelj B, Al-Chalabi A, Hortobágyi
Foundation grant 2012-A-015-FEL (J.S.Y.); and T and Shaw CE. p62 positive, TDP-43 negative,
an NIH-NIA Diversity Supplement to P50 neuronal cytoplasmic and intranuclear inclu-
AG023501 (J.S.Y., PI: B.L.M.). sions in the cerebellum and hippocampus de-
fine the pathology of C9orf72-linked FTLD and
Disclosure of conflict of interest MND/ALS. Acta Neuropathologica 2011; 122:
691-702.
None. [5] Bigio EH, Weintraub S, Rademakers R, Baker
M, Ahmadian SS, Rademaker A, Weitner BB,
Address correspondence to: Dr. Jennifer S Yokoya- Mao Q, Lee KH, Mishra M, Ganti RA and Me-
ma, Department of Neurology, University of Califor- sulam MM. Frontotemporal lobar degeneration
nia, 675 Nelson Rising Ln, Suite 190, San Francisco, with TDP-43 proteinopathy and chromosome
10 Am J Neurodegener Dis 2014;3(1):1-18C9ORF72 in behavioral and motor disease
9p repeat expansion in C9ORF72: clinicopath- from other noncoding repeat expansion disor-
ologic correlation. Neuropathology 2013; 33: ders? Curr Opin Neurol 2012; 25: 689-700.
122-33. [14] Cooper-Knock J, Shaw PJ and Kirby J. The wid-
[6] Cooper-Knock J, Hewitt C, Highley JR, Brocking- ening spectrum of C9ORF72-related disease;
ton A, Milano A, Man S, Martindale J, Hartley J, genotype/phenotype correlations and poten-
Walsh T, Gelsthorpe C, Baxter L, Forster G, Fox tial modifiers of clinical phenotype. Acta Neu-
M, Bury J, Mok K, McDermott CJ, Traynor BJ, ropathol 2014; 127: 333-45.
Kirby J, Wharton SB, Ince PG, Hardy J and [15] van Rheenen W, van Blitterswijk M, Huisman
Shaw PJ. Clinico-pathological features in amyo- MH, Vlam L, van Doormaal PT, Seelen M, Med-
trophic lateral sclerosis with expansions in ic J, Dooijes D, de Visser M, van der Kooi AJ,
C9ORF72. Brain 2012; 135: 751-764. Raaphorst J, Schelhaas HJ, van der Pol WL,
[7] Hsiung GYR, DeJesus-Hernandez M, Feldman Veldink JH and van den Berg LH. Hexanucleo-
HH, Sengdy P, Bouchard-Kerr P, Dwosh E, But- tide repeat expansions in C9ORF72 in the
ler R, Leung B, Fok A, Rutherford NJ, Baker M, spectrum of motor neuron diseases. Neurology
Rademakers R and Mackenzie IRA. Clinical 2012; 79: 878-882.
and pathological features of familial fronto- [16] Boeve BF, Boylan KB, Graff-Radford NR, DeJe-
temporal dementia caused by C9ORF72 muta- sus-Hernandez M, Knopman DS, Pedraza O,
tion on chromosome 9p. Brain 2012; 135: Vemuri P, Jones D, Lowe V, Murray ME, Dickson
709-722. DW, Josephs KA, Rush BK, Machulda MM,
[8] Mahoney CJ, Beck J, Rohrer JD, Lashley T, Mok Fields JA, Ferman TJ, Baker M, Rutherford NJ,
K, Shakespeare T, Yeatman T, Warrington EK, Adamson J, Wszolek ZK, Adeli A, Savica R, Boot
Schott JM, Fox NC, Rossor MN, Hardy J, B, Kuntz KM, Gavrilova R, Reeves A, Whitwell J,
Collinge J, Revesz T, Mead S and Warren JD. Kantarci K, Jack CR, Parisi JE, Lucas JA, Pe-
Frontotemporal dementia with the C9ORF72 tersen RC and Rademakers R. Characteriza-
hexanucleotide repeat expansion: clinical, tion of frontotemporal dementia and/or amyo-
neuroanatomical and neuropathological fea- trophic lateral sclerosis associated with the
tures. Brain 2012; 135: 736-750. GGGGCC repeat expansion in C9ORF72. Brain
2012; 135: 765-783.
[9] Yokoyama JS and Rosen HJ. Neuroimaging fea-
[17] Lesage S, Le Ber I, Condroyer C, Broussolle E,
tures of C9ORF72 expansion. Alzheimers Res
Gabelle A, Thobois S, Pasquier F, Mondon K,
Ther 2012; 4: 45.
Dion PA, Rochefort D, Rouleau GA, Durr A and
[10] Bede P, Bokde AL, Byrne S, Elamin M,
Brice A. C9orf72 repeat expansions are a rare
McLaughlin RL, Kenna K, Fagan AJ, Pender N,
genetic cause of parkinsonism. Brain 2013;
Bradley DG and Hardiman O. Multiparametric
136: 385-391.
MRI study of ALS stratified for the C9orf72
[18] Cooper-Knock J, Frolov A, Highley JR, Charles-
genotype. Neurology 2013; 81: 361-369.
worth G, Kirby J, Milano A, Hartley J, Ince PG,
[11] Byrne S, Elamin M, Bede P, Shatunov A, Walsh McDermott CJ, Lashley T, Revesz T, Shaw PJ,
C, Corr B, Heverin M, Jordan N, Kenna K, Lynch Wood NW and Bandmann O. C9ORF72 expan-
C, McLaughlin RL, Iyer PM, O’Brien C, Phukan sions, parkinsonism, and Parkinson disease: a
J, Wynne B, Bokde AL, Bradley DG, Pender N, clinicopathologic study. Neurology 2013; 81:
Al-Chalabi A and Hardiman O. Cognitive and 808-811.
clinical characteristics of patients with amyo- [19] Lindquist SG, Duno M, Batbayli M, Puschmann
trophic lateral sclerosis carrying a C9orf72 re- A, Braendgaard H, Mardosiene S, Svenstrup K,
peat expansion: a population-based cohort Pinborg LH, Vestergaard K, Hjermind LE, Stok-
study. Lancet Neurol 2012; 11: 232-240. holm J, Andersen BB, Johannsen P and Nielsen
[12] Irwin DJ, McMillan CT, Brettschneider J, Libon JE. Corticobasal and ataxia syndromes widen
DJ, Powers J, Rascovsky K, Toledo JB, Boller A, the spectrum of C9ORF72 hexanucleotide ex-
Bekisz J, Chandrasekaran K, Wood EM, Shaw pansion disease. Clin Genet 2013; 83: 279-
LM, Woo JH, Cook PA, Wolk DA, Arnold SE, Van 283.
Deerlin VM, McCluskey LF, Elman L, Lee VMY, [20] Jiao B, Guo JF, Wang YQ, Yan XX, Zhou L, Liu XY,
Trojanowski JQ and Grossman M. Cognitive de- Zhang FF, Zhou YF, Xia K, Tang BS and Shen L.
cline and reduced survival in C9orf72 expan- C9orf72 mutation is rare in Alzheimer’s dis-
sion frontotemporal degeneration and amyo- ease, Parkinson’s disease, and essential trem-
trophic lateral sclerosis. J Neurol Neurosurg or in China. Front Cell Neurosci 2013; 7: 164.
Psychiatr 2013; 84: 163-169. [21] Nuytemans K, Bademci G, Kohli MM, Beecham
[13] van Blitterswijk M, DeJesus-Hernandez M and GW, Wang L, Young JI, Nahab F, Martin ER, Gil-
Rademakers R. How do C9ORF72 repeat ex- bert JR, Benatar M, Haines JL, Scott WK, Zuch-
pansions cause amyotrophic lateral sclerosis ner S, Pericak-Vance MA and Vance JM.
and frontotemporal dementia: can we learn C9ORF72 Intermediate Repeat Copies Are a
11 Am J Neurodegener Dis 2014;3(1):1-18C9ORF72 in behavioral and motor disease
Significant Risk Factor for Parkinson Disease. [30] Takada LT and Sha SJ. Neuropsychiatric fea-
Ann Hum Genet 2013; 77: 351-363. tures of C9orf72-associated behavioral variant
[22] Le Ber I, Camuzat A, Guillot-Noel L, Hannequin frontotemporal dementia and frontotemporal
D, Lacomblez L, Golfier V, Puel M, Martinaud O, dementia with motor neuron disease. Alzheim-
Deramecourt V, Rivaud-Pechoux S, Millecamps ers Res Ther 2012; 4: 38.
S, Vercelletto M, Couratier P, Sellal F, Pasquier [31] Kertesz A, Ang LC, Jesso S, MacKinley J, Baker
F, Salachas F, Thomas-Anterion C, Didic M, Pa- M, Brown P, Shoesmith C, Rademakers R and
riente J, Seilhean D, Ruberg M, Wargon I, Blanc Finger EC. Psychosis and hallucinations in
F, Camu W, Michel BF, Berger E, Sauvee M, frontotemporal dementia with the C9ORF72
Thauvin-Robinet C, Mondon K, Tournier- mutation: a detailed clinical cohort. Cogn Be-
Lasserve E, Goizet C, Fleury M, Viennet G, Ver- hav Neurol 2013; 26: 146-154.
pillat P, Meininger V, Duyckaerts C, Dubois B [32] Landqvist Waldo M, Gustafson L, Nilsson K,
and Brice A. C9ORF72 repeat expansions in Traynor BJ, Renton AE, Englund E and Passant
the frontotemporal dementias spectrum of dis- U. Frontotemporal dementia with a C9ORF72
eases: a flow-chart for genetic testing. J Al- expansion in a Swedish family: clinical and
zheimers Dis 2013; 34: 485-499. neuropathological characteristics. Am J Neuro-
[23] Suzuki N, Maroof AM, Merkle FT, Koszka K, In- degener Dis 2013; 2: 276-286.
toh A, Armstrong I, Moccia R, Davis-Dusenbery [33] Sturm VE, Yokoyama JS, Seeley WW, Kramer
BN and Eggan K. The mouse C9ORF72 ortho- JH, Miller BL and Rankin KP. Heightened emo-
log is enriched in neurons known to degener- tional contagion in mild cognitive impairment
ate in ALS and FTD. Nat Neurosci 2013; 16: and Alzheimer’s disease is associated with
1725-1727. temporal lobe degeneration. Proc Natl Acad
[24] Smith Y, Bevan MD, Shink E and Bolam JP. Mi- Sci U S A 2013; 110: 9944-9949.
crocircuitry of the direct and indirect pathways
[34] Schmahmann JD and Pandya DN. Disconnec-
of the basal ganglia. Neuroscience 1998; 86:
tion syndromes of basal ganglia, thalamus,
353-387.
and cerebrocerebellar systems. Cortex 2008;
[25] Boeve BF and Graff-Radford NR. Cognitive and
44: 1037-1066.
behavioral features of c9FTD/ALS. Alzheimers
[35] Wojtas A, Heggeli KA, Finch N, Baker M, Deje-
Res Ther 2012; 4: 29.
sus-Hernandez M, Younkin SG, Dickson DW,
[26] Khan BK, Yokoyama JS, Takada LT, Sha SJ,
Graff-Radford NR and Rademakers R.
Rutherford NJ, Fong JC, Karydas AM, Wu T, Ke-
C9ORF72 repeat expansions and other FTD
telle RS, Baker MC, Hernandez MD, Coppola G,
gene mutations in a clinical AD patient series
Geschwind DH, Rademakers R, Lee SE, Rosen
HJ, Rabinovici GD, Seeley WW, Rankin KP, Box- from Mayo Clinic. Am J Neurodegener Dis
er AL and Miller BL. Atypical, slowly progressive 2012; 1: 107-118.
behavioural variant frontotemporal dementia [36] Adeli A, Savica R, Lowe VJ, Vemuri P, Knopman
associated with C9ORF72 hexanucleotide ex- DS, Dejesus-Hernandez M, Rademakers R,
pansion. J Neurol Neurosurg Psychiatr 2012; Fields JA, Crum BA, Jack CR, Petersen RC and
83: 358-364. Boeve BF. The GGGGCC repeat expansion in
[27] Simón-Sánchez J, Dopper EGP, Cohn-Hokke C9ORF72 in a case with discordant clinical
PE, Hukema RK, Nicolaou N, Seelaar H, de and FDG-PET findings: PET trumps syndrome.
Graaf JRA, de Koning I, van Schoor NM, Deeg Neurocase 2014; 20: 110-120.
DJH, Smits M, Raaphorst J, van den Berg LH, [37] Irish M, Devenney E, Wong S, Dobson-Stone C,
Schelhaas HJ, De Die-Smulders CEM, Majoor- Kwok JB, Piguet O, Hodges JR and Hornberger
Krakauer D, Rozemuller AJM, Willemsen R, Pi- M. Neural substrates of episodic memory dys-
jnenburg YAL, Heutink P and van Swieten JC. function in behavioural variant frontotemporal
The clinical and pathological phenotype of dementia with and without C9ORF72 expan-
C9ORF72 hexanucleotide repeat expansions. sions. Neuroimage Clin 2013; 2: 836-843.
Brain 2012; 135: 723-735. [38] Ling SC, Polymenidou M and Cleveland DW.
[28] Suhonen NM, Kaivorinne AL, Moilanen V, Bode Converging mechanisms in ALS and FTD: dis-
M, Takalo R, Hanninen T and Remes AM. Slow- rupted RNA and protein homeostasis. Neuron
ly progressive frontotemporal lobar degenera- 2013; 79: 416-438.
tion caused by the C9ORF72 repeat expan- [39] Polymenidou M, Lagier-Tourenne C, Hutt KR,
sion: a 20-year follow-up study. Neurocase Bennett CF, Cleveland DW and Yeo GW. Mis-
2014; [Epub ahead of print]. regulated RNA processing in amyotrophic lat-
[29] Williamson C, Alcantar O, Rothlind J, Cahn- eral sclerosis. Brain Res 2012; 1462: 3-15.
Weiner D, Miller BL and Rosen HJ. Stan- [40] Mori K, Lammich S, Mackenzie IRA, Forné I,
dardised measurement of self-awareness defi- Zilow S, Kretzschmar H, Edbauer D, Janssens
cits in FTD and AD. J Neurol Neurosurg J, Kleinberger G, Cruts M, Herms J, Neumann
Psychiatry 2010; 81: 140-145. M, Van Broeckhoven C, Arzberger T and Haass
12 Am J Neurodegener Dis 2014;3(1):1-18C9ORF72 in behavioral and motor disease
C. hnRNP A3 binds to GGGGCC repeats and is [49] Zhang D, Iyer LM, He F and Aravind L. Discov-
a constituent of p62-positive/TDP43-negative ery of Novel DENN Proteins: Implications for
inclusions in the hippocampus of patients with the Evolution of Eukaryotic Intracellular Mem-
C9orf72 mutations. Acta Neuropathol 2013; brane Structures and Human Disease. Front
125: 413-423. Genet 2012; 3: 283.
[41] Xu Z, Poidevin M, Li X, Li Y, Shu L, Nelson DL, Li [50] Levine TP, Daniels RD, Gatta AT, Wong LH and
H, Hales CM, Gearing M, Wingo TS and Jin P. Hayes MJ. The product of C9orf72, a gene
Expanded GGGGCC repeat RNA associated strongly implicated in neurodegeneration, is
with amyotrophic lateral sclerosis and fronto- structurally related to DENN Rab-GEFs. Bioin-
temporal dementia causes neurodegenera- formatics 2013; 29: 499-503.
tion. Proc Natl Acad Sci U S A 2013; 110: [51] Rubio-Texeira M and Kaiser CA. Amino acids
7778-83. regulate retrieval of the yeast general amino
[42] Ash PEA, Bieniek KF, Gendron TF, Caulfield T, acid permease from the vacuolar targeting
Lin WL, DeJesus-Hernandez M, van Blitterswijk pathway. Mol Biol Cell 2006; 17: 3031-3050.
MM, Jansen-West K, Paul JW, Rademakers R, [52] Schwenk BM, Lang CM, Hogl S, Tahirovic S,
Boylan KB, Dickson DW and Petrucelli L. Un- Orozco D, Rentzsch K, Lichtenthaler SF,
conventional translation of C9ORF72 GGGGCC Hoogenraad CC, Capell A, Haass C and Edbau-
expansion generates insoluble polypeptides er D. The FTLD risk factor TMEM106B and
specific to c9FTD/ALS. Neuron 2013; 77: 639- MAP6 control dendritic trafficking of lyso-
646. somes. EMBO J 2014; 33: 450-67.
[43] Mori K, Weng SM, Arzberger T, May S, Rent- [53] Brady OA, Zheng Y, Murphy K, Huang M and Hu
zsch K, Kremmer E, Schmid B, Kretzschmar F. The frontotemporal lobar degeneration risk
HA, Cruts M, Van Broeckhoven C, Haass C and factor, TMEM106B, regulates lysosomal mor-
Edbauer D. The C9orf72 GGGGCC Repeat Is phology and function. Hum Mol Genet 2013;
Translated into Aggregating Dipeptide-Repeat 22: 685-695.
Proteins in FTLD/ALS. Science 2013; 339: [54] Smith KR, Damiano J, Franceschetti S, Carpen-
1335-8. ter S, Canafoglia L, Morbin M, Rossi G, Parey-
[44] Meyer K, Ferraiuolo L, Miranda CJ, Likhite S, son D, Mole SE, Staropoli JF, Sims KB, Lewis J,
McElroy S, Renusch S, Ditsworth D, Lagier- Lin WL, Dickson DW, Dahl HH, Bahlo M and
Tourenne C, Smith RA, Ravits J, Burghes AH, Berkovic SF. Strikingly different clinicopatho-
Shaw PJ, Cleveland DW, Kolb SJ and Kaspar logical phenotypes determined by progranulin-
BK. Direct conversion of patient fibroblasts mutation dosage. Am J Hum Genet 2012; 90:
demonstrates non-cell autonomous toxicity of 1102-1107.
astrocytes to motor neurons in familial and [55] Van Der Zee J, Gijselinck I, Dillen L, Van Lan-
sporadic ALS. Proc Natl Acad Sci U S A 2014; genhove T, Theuns J, Engelborghs S, Philtjens
111: 829-832. S, Vandenbulcke M, Sleegers K, Sieben A,
[45] Belzil VV, Bauer PO, Prudencio M, Gendron TF, Bäumer V, Maes G, Corsmit E, Borroni B, Pado-
Stetler CT, Yan IK, Pregent L, Daughrity L, Bak- vani A, Archetti S, Perneczky R, Diehl-Schmid J,
er MC, Rademakers R, Boylan K, Patel TC, De Mendonça A, Miltenberger-Miltenyi G,
Dickson DW and Petrucelli L. Reduced C9orf72 Pereira S, Pimentel J, Nacmias B, Bagnoli S,
gene expression in c9FTD/ALS is caused by Sorbi S, Graff C, Chiang HH, Westerlund M,
histone trimethylation, an epigenetic event de- Sanchez-Valle R, Llado A, Gelpi E, Santana I,
tectable in blood. Acta Neuropathol 2013; Almeida MR, Santiago B, Frisoni G, Zanetti O,
126: 895-905. Bonvicini C, Synofzik M, Maetzler W, Vom Ha-
[46] Xi Z, Zinman L, Moreno D, Schymick J, Liang Y, gen JM, Schöls L, Heneka MT, Jessen F, Matej
Sato C, Zheng Y, Ghani M, Dib S, Keith J, Rob- R, Parobkova E, Kovacs GG, Ströbel T, Sarafov
ertson J and Rogaeva E. Hypermethylation of S, Tournev I, Jordanova A, Danek A, Arzberger
the CpG island near the G4C2 repeat in ALS T, Fabrizi GM, Testi S, Salmon E, Santens P,
with a C9orf72 expansion. Am J Hum Genet Martin JJ, Cras P, Vandenberghe R, De Deyn
2013; 92: 981-989. PP, Cruts M, Van Broeckhoven C, Van Der Zee
[47] Ciura S, Lattante S, Le Ber I, Latouche M, Tos- J, Gijselinck I, Dillen L, Van Langenhove T,
tivint H, Brice A and Kabashi E. Loss of func- Theuns J, Philtjens S, Sleegers K, Bäumer V,
tion of C9orf72 causes motor deficits in a ze- Maes G, Corsmit E, Cruts M, Van Broeckhoven
brafish model of Amyotrophic Lateral Sclerosis. C, Van Der Zee J, Gijselinck I, Dillen L, Van Lan-
Ann Neurol 2013; [Epub ahead of print]. genhove T, Philtjens S, Theuns J, Sleegers K,
[48] Therrien M, Rouleau GA, Dion PA and Parker Bäumer V, Maes G, Cruts M, Van Broeckhoven
JA. Deletion of C9ORF72 Results in Motor Neu- C, Engelborghs S, De Deyn PP, Cras P, Engel-
ron Degeneration and Stress Sensitivity in C. borghs S, De Deyn PP, Vandenbulcke M, Van-
elegans. PLoS One 2013; 8: e83450. denbulcke M, Borroni B, Padovani A, Archetti S,
13 Am J Neurodegener Dis 2014;3(1):1-18You can also read
