YEXNR-11579; No. of pages: 9; 4C: 5 Experimental Neurology xxx (2013) xxx–xxx

Contents lists available at ScienceDirect

Experimental Neurology journal homepage: www.elsevier.com/locate/yexnr

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Review

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John Hardy a,⁎, Ekaterina Rogaeva b a b

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Motor neuron disease and frontotemporal dementia: sometimes related, sometimes not

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Reta Lilla Weston Research Laboratories and Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK Tanz Centre for Research in Neurodegenerative Diseases and Department of Medicine, Division of Neurology, University of Toronto, 6 Queen's Park Crescent West, Toronto, ON M5S 3H2, Canada

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Article history: Received 16 September 2013 Revised 27 October 2013 Accepted 7 November 2013 Available online xxxx

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Over the last 5 years, several new genes have been described for both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). While it has long been clear that there are many kindreds in which the two diseases co-occur, there are also many in which the diseases segregate alone. In this brief review, we suggest that keeping the loci which lead to both diseases separate from those which lead to just one gives a clearer conclusion about disease mechanisms than lumping them together. The hypothesis that this separation leads to is that loci which cause both ALS and FTD affect the autophagic machinery leading to damaged protein aggregation and those which lead to just ALS are mainly involved in RNA/DNA metabolism. Two of the genes causing FTD alone (CHMP2B and GRN) are associated with damaged autophagy/lysosomal pathway. However, the third FTD gene (MAPT) maps to a different pathway, which perhaps is not surprising, since it is associated with a different (not p62-related) brain pathology characterized by abnormal tau filaments. We conclude that the current state of knowledge points to common mechanisms responsible for susceptibilities specific to neuronal classes. This includes the disruption of RNA metabolism in motor neurons and protein clearance, which is common between cortical and motor neurons. © 2013 Published by Elsevier Inc.

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Keywords: ALS FTD Genetics Pathology

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Introduction . . . . . . . . . FUS . . . . . . . . . . . . . TARDBP . . . . . . . . . . . C9orf72 (DENNL72) . . . . . VCP . . . . . . . . . . . . . SQSTM1 (p62) . . . . . . . . OPTN . . . . . . . . . . . . UBQLN2 . . . . . . . . . . . GRN . . . . . . . . . . . . CHMP2B . . . . . . . . . . . Synthesis . . . . . . . . . . Genes which cause ALS alone . Genes which cause FTD and ALS Genes which cause FTD alone . Conclusion . . . . . . . . . . Acknowledgments . . . . . . References . . . . . . . . . .

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Introduction

⁎ Corresponding author. E-mail address: [email protected] (J. Hardy).

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Recently, frontotemporal dementia (FTD; MIM: 600274) and amyo- 61 trophic lateral sclerosis (ALS; MIM: 612069) have been considered to 62 constitute a neurodegenerative syndrome, with patients presenting 63

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Please cite this article as: Hardy, J., Rogaeva, E., Motor neuron disease and frontotemporal dementia: sometimes related, sometimes not, Exp. Neurol. (2013), http://dx.doi.org/10.1016/j.expneurol.2013.11.006

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The heterozygous hexanucleotide (G4C2)n N 30 repeat expansion in the non-coding region of the C9orf72 gene clearly causes both FTD and ALS (MIM: 105550); and for both diseases genetic linkage and association has been reported (DeJesus-Hernandez et al., 2011; Renton et al., 2011). Currently, the repeat expansion accounts for 24– 37% of familial and 6–7% of sporadic cases in whites (Majounie et al., 2012; Rademakers, 2012). Hypotheses about the disease mechanism associated with the repeat expansion include toxic gain of function based on either the sequestering of RNA binding proteins by RNA foci consisting of pre-mRNA with the expansion (DeJesus-Hernandez et al., 2011); or the non-ATGinitiated translation from the expansion (in different reading frames) leading to the aggregation of dipeptide-repeat proteins in neurons (Ash et al., 2013; Mori et al., 2013). Another possibility is a loss of function mechanism, since the expansion is associated with hypermethylation of the CpG-island 5′ of the repeat (Xi et al., 2013) and ~50% reduction of C9orf72 mRNA in carriers (DeJesus-Hernandez et al., 2011). Of note, methylation changes were not detected in either normal or intermediate alleles (up to 43 repeats), raising the question of whether the cutoff of 30 repeats for pathologic alleles is adequate. Importantly, in several other disorders (e.g. Friedreich ataxia) repeat expansions lead to DNA hypermethylation and a down-regulation of gene expression (Xi et al., 2013). However, it seems unlikely that the main mechanism of the C9orf72 mutation is a loss of function because other segregating loss of function variants have not been found (e.g. stop codon mutations). Also, the only report of a homozygous repeat expansion in a patient with early-onset pure FTD rather supports a gain of toxic function mechanism, since the patient's clinical/pathological

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According to the Mutation Database, multiple mutations in the FUS gene (missense substitutions or in-frame small deletions/insertions) have been shown to segregate with ALS6 (MIM: 608030) (Cruts et al., 2012). The disease associated with FUS may present as an incompletely penetrant, recessive or sporadic disorder, however most of the families demonstrate an autosomal dominant mode of inheritance. The frequency of FUS mutations in familial ALS is ~5%. Half of the 23 pathogenic mutations affect the last FUS exon #15 containing a nuclear localization signal. Another mutation hot-spot is exon #6 encoding for a part of the Gly-rich low-complexity (prion-like) domain. Of note, there is substantial genetic variability in the FUS gene in normal controls (Huey et al., 2012), and some of the FUS mutations reported in patients have poor support for their pathogenic nature, such as lack of segregation with disease and/or autopsy results. For instance, FUS variants with a questionable pathogenic nature, such as Pro106Leu, Gln179His (Huey et al., 2012) and Met254Val (Van Langenhove et al., 2010), were reported in a few FTD patients. Hence, there is no strong evidence that FUS is genetically involved in FTD; however the brain pathology of ~5% of FTD patients is associated with FUS-proteinopathy (Sieben et al., 2012). The FUS protein is a component of the complex regulating sensors of DNA damage. Apart from DNA repair, FUS is also important for mRNA/microRNA metabolism (e.g. regulation of transcription and RNA splicing) (Vance et al., 2009). Normally FUS is mainly localized to the nucleus, while the mutant FUS protein is retained in the cytoplasm, thus interfering with nuclear function. Brain pathology of FUS-related ALS (with or without FUS mutations) is associated with motor neuron loss in the spinal cord, brainstem and motor cortex accompanied by nuclear and cytoplasmic aggregation of FUS in neurons and glial cells, as well as with diffuse ubiquitin positivity in nuclei, suggesting the presence of misfolded protein (Vance et al., 2009).

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Multiple heterozygous TARDBP mutations have been described as a cause of ALS10 (MIM: 612069), many of which have been shown to segregate with disease in an autosomal dominant mode of inheritance and explain ~3% of patients with familial ALS (Cruts et al., 2012). Almost all clearly pathogenic mutations (33 of 34) are missense substitutions (apart from a frame-shift mutation; Tyr374X), and affect codons 263 to 393 in the last TARDBP exon #6 encoding a Gly-rich lowcomplexity (prion-like) domain, similar to FUS. Only three mutations were reported in FTD (Lys263Glu; Asn267Ser) or FTD/ALS (Gly295Ser), without evidence of segregation with the FTD phenotype. One of the most common TARDBP mutations in ALS (Ala382Thr) was found in a homozygous state in two siblings from a consanguineous Italian family, one of which was diagnosed with Parkinson's disease (at age 61) followed by ALS/FTD six years later; while his 67 years old brother did not show any neurological signs (Mosca et al., 2012). This observation does not suggest a more severe phenotype in homozygous versus heterozygous TARDBP carriers. There are many functional similarities between the FUS and TARDBP gene that encodes the 43-kD TAR DNA-binding protein (TDP43), which is normally localized to the nucleus and involved in regulation of gene expression and splicing, while in disease it is relocated to cytoplasm leading to a loss of nuclear function (Neumann et al., 2006). A pathologic form of TDP43 is hyperphosphorylated, ubiquitinated, and cleaved, and constitutes a major component of the nuclear and cytoplasmic inclusions observed in neuronal and glial cells of the majority of ALS cases (with or without TARDBP mutations). Furthermore, brain pathology with TDP43-inclusions is a common link between several sporadic and inherited neurodegenerative conditions including FTD, as discussed below. Intriguingly, the results from transgenic TDP43 mice suggest that the detected signs of neurodegeneration are related to altered DNA/RNA-binding protein function rather than to toxic aggregation, since cytoplasmic TDP43 aggregates were absent in mutant mice (Wegorzewska et al., 2009).

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along a clinical spectrum. The fact that this can occur has been documented for ~ 80 years (Van Bogaert, 1925). Patients with pure FTD exhibit primary dementia often characterized by early behavioral problems and speech pathology; while patients with pure ALS are characterized by the degeneration of motor neurons affecting voluntary movements. Both syndromes may happen within the same family or even the same individual. The first identified mendelian cause of ALS is mutations in the SOD1 gene (Rosen et al., 1993), and the first identified mendelian cause of FTD is mutations in the MAPT gene (Hutton et al., 1998). In both of these conditions, while the phenotypes of SOD1 or MAPT mutation carriers have been variable, they have always been clearly within the spectra of ALS and FTD, respectively. However, the identification of mutations in TARDBP (Sreedharan et al., 2008) and FUS (Kwiatkowski et al., 2009) for ALS and mutations in GRN (Baker et al., 2006; Cruts et al., 2006) and CHMP2B (Skibinski et al., 2005) for FTD, followed by the apparent detection of mutations in these genes in patients with either of these disorders (Broustal et al., 2010; Cox et al., 2010; Huey et al., 2012; Parkinson et al., 2006; Van Langenhove et al., 2010) has added to the idea of an ALS–FTD continuum. In addition, the recent identification of mutations in VCP (Johnson et al., 2010; Watts et al., 2004), SQSTM1 (Fecto et al., 2011; Le Ber et al., in press; Rubino et al., 2012), OPTN (Kamada et al., 2013; Maruyama et al., 2010), UBQLN2 (Deng et al., 2011; Vengoechea et al., 2013) and especially the (G4C2)n N 30 repeat expansion in C9orf72 (DeJesus-Hernandez et al., 2011; Renton et al., 2011) in both disorders has also fostered the notion of a continuum. Setting aside the SOD1 and MAPT mutations, which clearly give rise to distinct disorders based on clinical and neuropathological features (ALS and FTD respectively), we need to systematically examine the evidence for the other genes mentioned above as causes of both diseases before we try and map them onto common biochemical pathways.

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Please cite this article as: Hardy, J., Rogaeva, E., Motor neuron disease and frontotemporal dementia: sometimes related, sometimes not, Exp. Neurol. (2013), http://dx.doi.org/10.1016/j.expneurol.2013.11.006

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Up to 20 broadly distributed heterozygous missense mutations in the VCP gene cause inclusion body myopathy with Paget disease of bone (PDB) and frontotemporal dementia (IBMPFD; MIM: 167320) (Watts et al., 2004) or ALS14 (MIM: 613954) with or without FTD

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(Johnson et al., 2010). Segregation of the mutations with all different disease phenotypes has been shown, although the phenotype in any individual with any particular mutation can vary significantly (Weihl et al., 2009). VCP encodes valosin-containing protein that is a member of a protein family known as the AAA + (ATPase associated with various activities). VCP activity is essential for multiple aspects of ubiquitindependent signaling, including proteasome-mediated degradation. The mutation mechanism is probably a complex loss of function, which resembling the effects of the TOR1A mutation causing dystonia by affecting the function of the Torsin-1A protein that belongs to the same AAA-ATPase family as VCP. The mutant Torsin-1A protein accumulates in large inclusions around the nucleus (Hewett et al., 2000), and downregulation of Torsin-1A leads to nuclear membrane abnormalities in neurons (Goodchild et al., 2005). VCP mutant proteins have a strong capacity to bind to small ubiquitinated inclusions that do not allow them to traffic to the perinuclear aggresome affecting the autophagic machinery responsible for the mass degradation of intracellular misfolded/damaged proteins and organelles (Ju et al., 2008). The brain pathology of carriers of VCP mutations is characterized by nuclear and cytoplasmic ubiquitin-positive TDP43 inclusions (negative for VCP), which supports the possibility that the mutations lead to loss of VCP function, such as affecting degradation of TDP43 (Neumann et al., 2007).

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features were severe but did not fall outside the usual disease spectrum. Yet, this patient had reduced expression of all known C9orf72 transcripts in the brain (Fratta et al., 2013). Hence, the two most plausible mechanisms are RNA toxicity, as has been demonstrated for a different repeat expansion in mytonic dystrophy (Timchenko, 2013), and inappropriate translation of the expanded repeat leading to aggregation of polydipeptides in the form of p62 inclusions (Ash et al., 2013; Mori et al., 2013). It is also possible that the disease mechanism is multifactorial. Indeed, it is tempting to speculate that the broad phenotypic variability in C9orf72 patients (e.g. ALS vs FTD) could be explained by the extent of the contribution from the different disease mechanisms. Finally, the repeat size itself could be an explanation for the wide-range of disease symptoms. However, assessment of the C9orf72 repeat number is technically challenging, since repeatprimed PCR can only resolve the size for expansions of up to 50 repeats. Although in a few published cases, the size of the expansion was estimated by Southern blot (700–2000 repeats) (DeJesus-Hernandez et al., 2011). Recently the largest Southern blot study of 84 individuals with FTD, ALS or FTD/ALS evaluated whether C9orf72 expansion size is associated with disease severity or phenotype (van Blitterswijk et al., 2013). It demonstrated that repeat length in different tissues from the same patient could be highly variable in some individuals, indicating somatic heterogeneity; while for other patients the expansion is almost of the same length in the brain and blood. Intriguingly, this study detected that on average, expansion lengths in the frontal cortex were longer (~ 5250 repeats) than in blood (~ 2717 repeats) and cerebellum (~ 1667 repeats). Yet, within these tissues there was no association between repeat length and disease phenotype in entire dataset. In the FTD subgroup, longer expansions in frontal cortex surprisingly correlated with older age at onset; which might be driven by age at sample collection, because repeat sizes could lengthen with age. Another intriguing observation was that expansion length in cerebellum was associated with a survival disadvantage. This is of interest, since p62positive neuronal inclusions (highly specific to C9orf72 patients) are mainly detected in the cerebellum (Al-Sarraj et al., 2011). Intriguingly, this area of the brain is unaffected by neuronal loss. The brain pathology of patients with a C9orf72 repeat expansion shows the typical aggregates of phosphorylated TDP43, but is more specifically characterized by abundant TDP43-negative cytoplasmic inclusions in neurons (Al-Sarraj et al., 2011). The latter p62-inclusions are mainly detected in the hippocampus (pyramidal cell layer) and cerebellum (granular cell layer, molecular layer and Purkinje cells). This brain pathology is so distinct that cases with the expansion could be identified blindly to genotype by examining p62-immunohistochemistry of the cerebellum and hippocampus. Recently it was reported that these inclusions consist of aggregated dipeptide-repeat proteins translated from the repeat expansion, as mentioned above (Mori et al., 2013). In addition, these inclusions could be identified with antibodies for ubiquitin, p62 and/or ubiquilin-2 (Brettschneider et al., 2012). Intriguingly, p62 is encoded by SQSTM1, while ubiquilin-2 is encoded by UBQLN2; both of these genes if mutated cause ALS/FTD, as discussed below. Thus far, nothing is known about the normal function of C9orf72. However, a recent homology search showed that C9orf72 is distantly related to DENN domain proteins (DENN stands for ‘differentially expressed in normal and neoplastic cells’), which are GDP/GTP exchange factors that activate Rab-GTPases. It suggests that C9orf72 likely regulates membrane traffic in conjunction with Rab-GTPase switches (Levine et al., 2013).

Similar to VCP, the heterozygous missense or nonsense mutations in the SQSTM1 gene cause PDB (MIM: 602080) (Laurin et al., 2002). More recently, up to 20 different missense or truncating mutations have been identified in FTD (Le Ber et al., in press; Rubino et al., 2012) and ALS (Fecto et al., 2011) patients of different European or Japanese origin. The frequency of the SQSTM1 mutations in FTD and ALS is ~ 3% with two families reported to segregate the mutations with FTD, including Pro387Leu mutation detected in three affected siblings (Le Ber et al., in press). Some of these mutations were reported in patients with PDB and likely act through a common disease mechanism — the autophagic degradation of ubiquitinated protein aggregates affecting a formation/ clearance of misfolded proteins (Kwok et al., 2013; Teyssou et al., 2013). For instance, in a UK study the father of the proband with the Glu155Lys mutation was diagnosed with PDB, and a carrier of the Pro392Leu mutation developed symptoms of both ALS and PDB. Similarly, a French study of SQSTM1 detected the Ala390X and Pro392Leu mutations in ALS patients with concomitant PDB, both of which have been previously described in pure PDB (Teyssou et al., 2013). Notably, the Pro392Leu is the most common SQSTM1 mutation in ALS, and its pathogenicity is supported by a causal role in PDB where there is evidence of transmission of the mutation with disease in multiple families (Kwok et al., 2013). PDB mutations mainly affect the ubiquitin associated domain of p62 (codons 335–427), while the ALS and FTD mutations are broadly distributed throughout the SQSTM1 gene (codons 33–439). However, the coexistence of PDB with ALS and FTD could be underestimated, since PDB is often asymptomatic and mainly diagnosed based on radiographic results. The brain pathology of FTD patients with SQSTM1 mutations has not been published. However, recently neuropathology results were reported for three ALS patients with two novel possible pathogenic mutations (Met87Val, Lys102Glu), as well as a pathogenic mutation previously found in several PDB cases (Cly351-Pro388 del, also known as A390X) (Teyssou et al., 2013). The results revealed the presence of large round p62 inclusions in motor neurons, and immunoblot analysis showed increased p62 and TDP43 protein levels in the spinal cord. These neuronal and glial inclusions were found in both cortex and spinal cord. In addition, two cases with Lys102Glu and A390X had atrophy of the frontal lobe that confirms the overlap between ALS and FTD in patients with

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Please cite this article as: Hardy, J., Rogaeva, E., Motor neuron disease and frontotemporal dementia: sometimes related, sometimes not, Exp. Neurol. (2013), http://dx.doi.org/10.1016/j.expneurol.2013.11.006

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UBQLN2 is intronless gene on chromosome Xp11.21. Heterozygous missense mutations are responsible for ALS15 (MIM: 300857) with or without FTD (Deng et al., 2011). UBQLN2 mutations can affect males and females and display high phenotypic variability within the same family (e.g. ALS, FTD, spastic paraplegia and multiple sclerosis) (Vengoechea et al., 2013). In large families, mutations segregate with ALS and/or FTD in an apparently autosomal dominant mode (without male-to-male transmission). UBQLN2 is a member of the ubiquitin-like protein family characterized by a ubiquitin-like domain (that bind subunits in the proteasome) and a ubiquitin-associated domain (that binds to polyubiquitin chains — a marker for degradation by the proteasome) (Vengoechea et al., 2013). All pathological UBQLN2 mutations affect proline residues in the ProXX repeat region, leading to a deficiency in protein degradation. The spinalcord pathology of UBQLN2 carriers is associated with skein-like inclusions immunoreactive to UBQLN2, ubiquitin, p62, TDP43, FUS and OPTN.

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Rare null/nonsense and missense mutations in the gene encoding optineurin (OPTN) cause both recessive and dominant ALS12 (MIM: 613435). About 20 different very rare (b 1%) OPTN mutations have been identified in ALS patients (http://alsod.iop.kcl.ac.uk/Als/misc/ dataDownload.aspx). A few loss of function OPTN mutations (e.g. exon 5 deletion) have been shown to segregate with ALS in siblings from consanguineous Japanese families (Maruyama et al., 2010). In addition, OPTN mutations are responsible for adult-onset glaucoma (MIM: 137760), however their positions are distinct from ALS mutations, suggesting different disease mechanism. The brain pathology of ALS cases with OPTN mutations is available for only a few patients. In the original study, the carrier of the Glu478Gly mutation was reported to have intracytoplasmic OPTN-positive inclusions in motor neurons, as well as loss of myelin from the corticospinal tract and of the anterior horn cells (Maruyama et al., 2010). However, an independent report of an ALS patient with the same heterozygous Glu478Gly mutation did not detect OPTN inclusions, but revealed typical TDP43/p62/ubiquitin cytoplasmic inclusions in motor neurons and glia. Importantly, this patient presented with clinical signs of FTD (mood and personality changes) supported by temporal lobe atrophy (Ito et al., 2011). Neuropathological results were also reported for two ALS patients with homozygous Gln398X mutation with one of them presented with FTD-like symptoms (e.g. temporal/frontal lobe dysfunction) (Kamada et al., 2013). Hence, OPTN could cause ALS/FTD, however the OPTN mutations in pure FTD cases are not reported (Rollinson et al., 2012). The TDP43 pathology of Gln398X was similar to that of a dominant Glu478Gly mutation. Both cases revealed widespread degeneration of the basal ganglia, cortical and spinal motor neurons. TDP43 neuronal/glial cytoplasmic inclusions were observed throughout the central nervous system. Again, immunoreactivity for OPTN was not detected, consistent with nonsense-mediated mRNA decay of mutant OPTN, which suggests that TDP43 deposits and disease symptoms are result of the loss of OPTN function. OPTN regulates various physiological processes. Similar to SQSTM1/ p62, OPTN is an autophagy receptor that binds to ubiquitin chains and autophagy modifier proteins (Wild et al., 2011), and silencing of OPTN leads to impaired autophagy. Of note, a genome-wide association study in patients with PDB (free from SQSTM1 mutations), identified significant association with the OPTN locus (Albagha et al., 2010). Such an observation is important, since it points to a strong functional link between PDB-related ALS/FTD genes (OPTN, SQSTM1 and VCP); and as we mentioned above, the coexistence of PDB with other ALS/ FTD genes could be underrated due to the frequent asymptomatic presentation of PDB. Furthermore, the ALS-linked OPTN mutations result in activation of nuclear factor kappa B (NF-κB) that is a major transcription factor regulating numerous genes involved in innate immunity, cell

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survival/death, and inflammation (Akizuki et al., 2013; Maruyama et al., 382 2010). 383

Thus far, the 69 different heterozygous pathogenic GRN mutations are broadly distributed throughout the gene, including a noncoding exon and were reported to segregate with FTD in an autosomal dominant mode of inheritance (MIM: 607485) (Cruts et al., 2012). The reported frequency of GRN mutations in familial FTD is up to 10%. Most of the mutations are loss of function aberrations resulting in nonsense-mediated mRNA decay. While GRN variants have been reported in a few ALS patients, these have not been clear loss of function changes and no segregation with ALS has been reported (e.g. Arg110Gln was detected in a single ALS case). Missense GRN variants have also been reported both in Alzheimer's disease patients and in controls. Thus, there is no data implicating GRN in the pathogenesis of mendelian ALS. Yet, the brain pathology of GRN carriers is similar to ALS cases with TARDBP mutations, and is characterized by nuclear/cytoplasmic TDP43 neuronal and glial inclusions (Baker et al., 2006; Cruts et al., 2006). A recent report revealed a remarkably different phenotype associated with homozygous GRN mutations, suggesting a lysosomal function for GRN (Smith et al., 2012). A homozygous frame-shift deletion in GRN was found in two siblings of 26 and 28 years of age diagnosed with neuronal ceroid lipofuscinosis-11 (CLN11; MIM: 614706) — a neurodegenerative disease characterized by the storage of abnormal lipopigment in lysosomes. In their 20s both sibs presented with visual failure, followed by retinal dystrophy, seizures, cerebellar ataxia, and cerebellar hypoplasia (only one of them presented with cognitive decline). This finding resembles the observation in GBA-related disorders, when homozygous mutations cause Gaucher disease (lysosomal storage disorder), while heterozygous mutations are associated with Parkinson's disease and dementia with Lewy bodies (Nalls et al., 2013). The GRN protein has multiple roles. It influences inflammation, embryogenesis, and tumorigenesis, and functions as a wound-related growth factor (He et al., 2003). A major source of GRN in the brain is microglial cells, with elevated GRN levels in activated microglia after neuronal injury (Hu et al., 2010). The GRN-linked disease mechanism is likely acting via the endosomal/autophagosomal/lysosomal pathway (Hu et al., 2010). For instance, the GRN protein and VCP (as discussed below) might function to clear TDP43 aggregates via the autophagy/ lysosomal pathway, which could be compromised as a result of the deficiency in these proteins. Indeed, GRN is co-regulated with lysosomal genes, since there is accelerated brain lipofuscinosis in mice lacking GRN and homozygous loss of function mutations in GRN cause ceroid lipofuscinosis in humans (Smith et al., 2012).

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SQSTM1 mutations. Surprisingly, all three cases had neuronal loss and gliosis in the substantia nigra (without Lewy bodies). The SQSTM1 gene encodes the ubiquitin-binding p62 protein — a multifunctional protein that forms stable dimers important for its ability to bind ubiquitin. The p62 protein is a common component of cytoplasmic inclusions in a wide-range of protein aggregation diseases (e.g. neurodegenerative, liver, or muscle disorders) and linked to both major protein degradation mechanisms: the ubiquitin-proteasome system and autophagy (Gal et al., 2009; Pikkarainen et al., 2008). SQSTM1 and VCP mutations could target similar cellular pathways and cause the disease by compromising ubiquitin binding. The ALS/FTD mutations may thus alter the protein–protein interactions or dimerization process, promoting protein aggregation (Rubino et al., 2012). Genetic ablation of p62 in a mouse model suppressed the appearance of ubiquitin-positive protein aggregates in hepatocytes and neurons, indicating that p62 plays an important role in inclusion body formation (Komatsu et al., 2007).

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Fig. 1. The levels of expression of the genes linked to ALS and/or FTD in different anatomical categories of the nervous system according to Genevestigator (https://www.genevestigator.com). For each anatomical category, the figure displays the average expression values that are scaled to the total abundance of the transcripts. The outer lines (whiskers) for each box plots indicate maximum and minimum values outside the upper and lower quartiles (red box). The vertical line within each red box represents the median and dots (stars) are outliers. The IQR (at the top of graphs) indicates that the interquartile range is equal to the difference between the upper and lower quartiles.

J. Hardy, E. Rogaeva / Experimental Neurology xxx (2013) xxx–xxx

Please cite this article as: Hardy, J., Rogaeva, E., Motor neuron disease and frontotemporal dementia: sometimes related, sometimes not, Exp. Neurol. (2013), http://dx.doi.org/10.1016/j.expneurol.2013.11.006

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Table 1 A summary of genetic, clinical and brain histopathology data together with the possible target of mutations in ALS and/or FTD (the black boxes capture the suggested continuum in all three categories). Genetics of ALS and/or FTD Type of mutations

Clinical presentation

Brain pathologya

Likely pathological effect

SOD1

~20%

Mainly missense

ALS

SOD1/p62

Toxic aggregation

FUS

~5%

Mainly missense, & in–frame small deletions/insertions

ALS

FUS/p62

DNA/RNA metabolism

TARDBP (TDP43)

~3%

Mainly missense, & one truncating

ALS

TDP43/p62

DNA/RNA metabolism

C9orf72

~30%

G4C2–repeat expansion

ALS, FTD

TDP43/p62, p62/repeat– dipeptides, UBQLN2

Toxic RNA (?) Toxic aggregation(?) Low C9orf72 expression (?)

Missense

FTD, ALS, IBMPFD

TDP43/p62

Autophagy

SQSTM1 (p62)

~3%

Missense and nonsense

FTD, ALS, PDB

TDP43/p62

Autophagy

OPTN

Rare

Missense and nonsense (haploinsufficiency)

ALS/FTD, glaucoma PDB (by GWAS)

TDP43/p62

Autophagy

UBQLN2

Rare

Missense

ALS, FTD, SP, MS

TDP43/p62, UBQLN2, FUS, OPTN

Autophagy

~10%

Nonsense (haploinsufficiency)

FTD, CLN11

TDP43/p62

Autophagy/lysosomal pathway

CHMP2B

Rare

C–terminal truncation of the CHMP2B

FTD

p62

Autophagy/lysosomal pathway

MAPT

~10%

Missense and splicing of exon 10

FTD

Abnormal tau filaments (tangles)

Toxic aggregation (defect in neuronal cytoskeleton)

a

Heterozygous mutations in CHMP2B are very rare and cause FTD3 (MIM: 600795). In the original Danish family with autosomal dominant FTD, the sole segregating mutation was a C-terminal nonsense change which deleted the extreme C-terminal of the protein affecting the acidic domain (Skibinski et al., 2005). Subsequently, other similar C-terminal deleting mutations have been identified which also segregate with disease (van der Zee et al., 2008). These mutations have clear and reproducible effects on endosomal vesicle trafficking (Urwin et al., 2010). CHMP2B encodes a component of ESCRT-III complex involved in endosomal structure that fuses with the lysosome to degrade endocytosed proteins. Endosomal pathology was detected in the brains of CHMP2B patients (large vacuoles in the cytoplasm of cortical neurons); and functional studies demonstrated that CHMP2B mutants disrupt the fusion of endosomes with lysosomes (Urwin et al., 2010). CHMP2B variants have been reported in ALS cases, but these have been missense variants (Thr104Asn and Gln206His) which do not segregate with disease (Cox et al., 2010; Parkinson et al., 2006) and, as yet, have not been reported to have any effect on endosomal vesicle recycling. Thus, the implication that CHMP2B mutations cause ALS is not secure. Furthermore, the distinctive brain pathology in carriers of CHMP2B mutations has not been reported in ALS (Ghazi-Noori et al., 2012; Holm et al., 2007). In cases from the Danish family variable numbers of small, round, p62/ubiquitin-positive cytoplasmic inclusions (negative for TDP43 and FUS) were present in the dentate granule layer of the hippocampus and frontal/temporal cortical neurons. Mouse models provided evidence for a gain of toxic function mechanism in CHMP2B-linked FTD, since human-like neuropathology was

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Genes which cause ALS alone

493

474 475 476 477 478 479

482 483 484 485 486 487 488 489 490 491 492

In the ALS alone category there are genes involved in RNA/DNA metabolism (FUS and TDP43). In this regard it is worth noting that recessive loss of function mutations in two other genes important for RNA metabolism, GLE1 (the mRNA export mediator) and SMN1 (needed for assembly of small nuclear ribonucleoprotein complexes) give rise to severe degeneration of motor neurons (Lunn and Wang, 2008; Nousiainen et al., 2008). Thus, these data together suggest that motor neurons have specific requirements for RNA processing and disrupting these processes leads to a fairly selective loss. SOD1 encodes a ubiquitously expressed free-radical scavenging enzyme that does not fit easily within the RNA metabolism framework and clearly could cause motor neuron loss by an entirely distinct mechanism. ALS caused by SOD1 mutations is not believed to be related to changes in normal enzymatic activity. Animal model work has suggested that this form of disease is made worse by the expression of the mutant protein in other non-neuronal cells in the CNS (Yamanaka et al., 2008) suggesting that pathogenesis is dependent on the amount of mutant protein and results from a toxic gain of function, probably in the extracellular compartment.

494 Q11

Genes which cause FTD and ALS

513

Based on the data summarized in Table 1 the strongest clinical, brain histopathology and functional overlap is observed for VCP, OPTN, SQSTM1 and UBQLN2 genes, suggesting that these genes represent the core of the ALS/FTD continuum. Intriguingly, mutations in three of them (VCP, OPTN and SQSTM1) cause PDB, in addition to ALS and FTD. These mutations are believed to cause disease by inhibiting protein degradation through autophagy and the ubiquitin-proteasome system (Meyer et al., 2012). UBQLN2 is involved in the same processes (Deng et al., 2011). As noted above, two of the most likely disease mechanisms proposed for the C9orf72 expansion: either a toxic mRNA or a build-up of polydipeptides (Ash et al., 2013; Mori et al., 2013). These data suggest that the FTD/ALS disease continuum is one of inhibited or overloaded protein degradation. It is tempting to speculate that defects in autophagy allow the pathology to be self-propagating and spread to different brain regions in a prion-like manner.

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In general, the inclusions are ubiquitin-positive and contain the ubiquitin binding protein p62 (Pikkarainen et al., 2008). Abbreviations: frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD), Paget disease of bone (PDB), spastic paraplegia (SP), multiple sclerosis (MS), neuronal ceroid lipofuscinosis-11 (CLN11), and genome-wide association study (GWAS).

CHMP2B

448 449

One possibility to explain FTD versus ALS is gene expression pattern, such as high level of expression of FTD genes in frontal lobe versus spinal cord. However, according to Genevestigator expression database (https://www.genevestigator.com/gv/biomed.jsp), all genes within the spectra of ALS and FTD are robustly expressed in different human tissues, including different parts of the brain (Fig. 1). Another and a more likely explanation of the phenotypic split is the effect of the pathological mutations on the specific function of the gene product. The genetic and pathological data as well as mutation effect are briefly summarized in Table 1. This grouping of genes by outcome leads directly to hypotheses about the functions which are impaired in the different categories.

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GRN

444

446 447

480

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Rare

Synthesis

R O

VCP

472 473

F

Frequency in familial cases

C

t1:6 t1:7 t1:8 t1:9

Gene

E

t1:5

Continuum based on:

observed only in transgenic mice expressing C-terminally truncated mutant CHMP2B, but not in knockout mice (Ghazi-Noori et al., 2012). The formation of these inclusions is likely due to impaired protein degradation through the autophagy/endosome/lysosome pathways. In general, p62 protein is an autophagy marker and observed in many different types of disease-associated neuronal/glial ubiquitin-inclusions (Pikkarainen et al., 2008). Hence, it is important to determine the specific protein targeted by p62 for autophagy in the brain of CHMP2B patients.

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t1:1 t1:2 t1:3 t1:4

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In this review, we suggest that by critical consideration of the phenotypes caused by mutations in ALS and FTD we can group them more usefully than if we just accept the literature as it is presented. When we do this, we see patterns which point to common mechanisms responsible for susceptibilities specific to neuronal classes. This includes the disruption of RNA metabolism in motor neurons and protein clearance, which is common between cortical and motor neurons.

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Acknowledgments

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This work was supported by the W. Garfield Weston Foundation and Ontario Research Fund (ER) and the Reta Lilla Weston Foundation (JH).

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References

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Two of the genes causing FTD alone (CHMP2B and GRN) are associated with a damaged autophagy/lysosomal pathway, similar to the ALS/ FTD genes and therefore, belong to the periphery of the continuum. Such a conclusion is supported by overlapping brain pathology features: carriers of CHMP2B and GRN mutations are characterized by cytoplasmic p62-positive inclusions. In contrast, the third FTD gene (MAPT that encodes tau) maps to a different pathway, which perhaps is not surprising, since it is associated with a different (not p62-related) brain pathology characterized by abnormal hyperphosphorylated tau filaments. Dominant MAPT mutations cause FTD with parkinsonism. Importantly, tau-pathology is a feature of many diseases (tauopathies), the most frequent of which is Alzheimer's disease (Spillantini and Goedert, 2013). This suggests that the pathway by which MAPT mutations lead to FTD is related to a pathway common to the pathogenesis of many neurodegenerative diseases but not with other forms of FTD or FTD/ALS. Nevertheless, the autophagy system is considered a therapeutic possibility, since tau-aggregates might be degraded by the autophagy/lysosome system, while soluble tau is degraded by the proteasome system. Indeed, in a mouse FTD model or neuronal cell model of tauopathy, the activation of autophagy reduced the concentration of insoluble tau, the number of tau inclusions, and improved nerve cell survival (Spillantini and Goedert, 2013). GRN mutations, unlike all the other mutations described in this review, give rise to a markedly asymmetric disease: indeed this is a distinguishing feature of this form of FTD (Rohrer and Warren, 2011). The role of GRN in damage repair is clear (Hu et al., 2010) and, given that GRN mutations typically have disease onset after late middle age, this leads to the suggestion that they have their clinical effects at a time when damage repair might be initiated by (for example) minor vascular damage and that the asymmetry reflects the site of this minor initiating damage.

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Motor neuron disease and frontotemporal dementia: sometimes related, sometimes not.

Over the last 5 years, several new genes have been described for both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). While it ...
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