**2.1 ALS1 (SOD1)**

Linkage analysis in autosomal-dominant fALS pedigrees associated the copper-zinc superoxide dismutase (*SOD1*) gene on chromosome 21q to ALS. Several point mutations in

<sup>\*</sup> Corresponding authors

Genetics of Amyotrophic Lateral Sclerosis 481

*SOD1* that co-segregated with the disease were identified in several of these pedigrees (Rosen et al., 1993). To date, over 150 different mutations in *SOD1* have been identified (see http://alsod.iop.kcl.ac.uk). Mutations have been reported in ~20% of fALS patients and in

The SOD1 protein is a cytoplasmic enzyme that converts superoxide radicals, a by-product of oxidative phosphorylation, to hydrogen peroxide and molecular oxygen. The exact mechanism by which *SOD1* mutations lead to ALS pathology is unknown although several toxic properties of mutant SOD1 such as aberrant oxidative stress, protein instability, and mitochondrial damage have been proposed to be causative (reviewed in Pasinelli and Brown, 2006). Interestingly, the presence of mutant SOD1 in non-neuronal cells contributes to pathogenesis and is needed for disease progression (Ilieva et al., 2009). *SOD1* mutations most likely result in a toxic gain of function pathology since *SOD1* knockout mice do not develop motor neuron degeneration whereas transgenic mice overexpressing mutant SOD1 show motor neuron degeneration and ALS-like pathology (Gurney et al., 1994; Reaume et

ALS2 is an autosomal recessive form of juvenile ALS that was first reported in a large consanguineous Tunisian kindred and linkage analysis in this family associated locus 2q33 q35 to ALS (Hentati et al., 1994). This led to the discovery of causal mutations in the gene encoding ALSin (Hadano et al., 2001; Yang et al., 2001). Mutations in *ALSin* have been

ALSin is a Rab5 and Rac1 guanine exchange factor that acts as a regulator of endosomal/membrane trafficking. The protein is able to promote neurite outgrowth in neuronal cultures through activation of the small GTPase Rac1 (Otomo et al., 2003; Topp et al., 2004). Overexpression of ALSin protects cultured motor neuronal cells from mutant SOD1 toxicity suggesting a neuroprotective role. Mutations in *ALSin* may induce a loss of this neuroprotective function (Kanekura et al., 2004). *ALSin* knockout mice do not develop overt motor neuron disease but degeneration of the corticospinal tract has been reported

Linkage to chromosome 18q21 was identified in a large European family of which 20 members had autosomal-dominant ALS (Hand et al., 2002). This region contains 50 genes

ALS4 is a rare, childhood- or adolescent-onset, autosomal dominant disease, which is also known as distal hereditary motor neuronopathy with pyramidal features. Linkage to chromosome 9q34 was found in a large family from the USA with 49 affected members (Chance et al., 1998). Sequencing of 19 genes in this locus revealed that missense mutations in the senataxin (*SETX*) gene were the cause of ALS4 in several families (Chen et al., 2004). Since then, mutations have been identified in additional ALS patients from China, Italy and the USA (Avemaria et al., 2011; Hirano et al., 2011; Zhao et al., 2009). Interestingly, mutations in *SETX* leading to a premature termination in the protein product have also been

scarcely reported and do not appear to be a common cause of ALS.

but the causal mutation at this locus remains to be identified.

identified in ataxia oculomotor apraxia 2 (Moreira et al., 2004).

1-4% of sALS patients (Pasinelli and Brown, 2006; Valdmanis and Rouleau, 2008).

al., 1996).

**2.2 ALS2 (ALSin)** 

**2.3 ALS3 (18q21)** 

**2.4 ALS4 (SETX)** 

(Cai et al., 2008; Hadano et al., 2006).


AD = Autosomal dominant, AR = Autosomal recessive, XD = X-linked dominant, FTD = frontotemporal dementia, SMA = spinal muscular atrophy, N.K. = not known, FTDP = frontotemporal dementia with parkinsonism

Table 1. Classification of familial ALS.

**ALS3** 18q21 N.K. - AD Typical ALS, disease onset in legs

**ALS5** 15q15-21 *SPG11* Spatacsin AR Juvenile onset, slowly progressive

**ALS6** 16p11.2 *FUS* Fused in sarcoma AD/AR Typical ALS

**ALS7** 20p13 N.K. - AD Typical ALS

**ALS12** 10p13 *OPTN* Optineurin AD/AR Adult onset

**ALS-FTD1** 9q21-22 N.K. - AD ALS, FTD

Chromosome 9 open reading frame 72

Microtubuleassociated protein tau

**ALS-X** Xcen N.K. - XD Adult onset

AD = Autosomal dominant, AR = Autosomal recessive, XD = X-linked dominant, FTD = frontotemporal dementia, SMA = spinal muscular atrophy, N.K. = not known, FTDP = frontotemporal dementia with

**ALS9** 14q11 *ANG* Angiogenin AD Typical ALS, frontotemporal

dismutase AD/AR Typical ALS

protein B AD Typical ALS, SMA and atypical ALS

phosphatase AD Adult onset, prominent corticospinal

protein AD Adult onset with or without FTD

AD ALS, FTD

AD Adult onset with FTD

protein AD Typical ALS

Juvenile onset, slowly progressive, predominantly upper motor neuron signs

Childhood/Adolescent onset, slowly progressive, no respiratory and bulbar involvement

dementia, Parkinson's disease

tract signs

*Disease Locus Gene Protein Inheritance Clinical features* 

**ALS1** 21q22 *SOD1* Cu/Zn superoxide

**ALS8** 20q13 *VAPB* VAMP-associated

**ALS10** 1q36 *TARDBP* TAR-DNA binding

**ALS11** 6q21 *FIG4* PI(3,5)P(2)5-

**ALS14** 9p13-p12 *VCP* Valosin-containing

**ALS-FTD2** 9p13.2-21.3 *C9ORF72*

**FTDP** 17q21.1 *MAPT*

Table 1. Classification of familial ALS.

**ALS-**

parkinsonism

**ALS2** 2q33 *ALSin* ALSin AR

**ALS4** 9q34 *SETX* Senataxin AD

*Name of* 

*SOD1* that co-segregated with the disease were identified in several of these pedigrees (Rosen et al., 1993). To date, over 150 different mutations in *SOD1* have been identified (see http://alsod.iop.kcl.ac.uk). Mutations have been reported in ~20% of fALS patients and in 1-4% of sALS patients (Pasinelli and Brown, 2006; Valdmanis and Rouleau, 2008).

The SOD1 protein is a cytoplasmic enzyme that converts superoxide radicals, a by-product of oxidative phosphorylation, to hydrogen peroxide and molecular oxygen. The exact mechanism by which *SOD1* mutations lead to ALS pathology is unknown although several toxic properties of mutant SOD1 such as aberrant oxidative stress, protein instability, and mitochondrial damage have been proposed to be causative (reviewed in Pasinelli and Brown, 2006). Interestingly, the presence of mutant SOD1 in non-neuronal cells contributes to pathogenesis and is needed for disease progression (Ilieva et al., 2009). *SOD1* mutations most likely result in a toxic gain of function pathology since *SOD1* knockout mice do not develop motor neuron degeneration whereas transgenic mice overexpressing mutant SOD1 show motor neuron degeneration and ALS-like pathology (Gurney et al., 1994; Reaume et al., 1996).

### **2.2 ALS2 (ALSin)**

ALS2 is an autosomal recessive form of juvenile ALS that was first reported in a large consanguineous Tunisian kindred and linkage analysis in this family associated locus 2q33 q35 to ALS (Hentati et al., 1994). This led to the discovery of causal mutations in the gene encoding ALSin (Hadano et al., 2001; Yang et al., 2001). Mutations in *ALSin* have been scarcely reported and do not appear to be a common cause of ALS.

ALSin is a Rab5 and Rac1 guanine exchange factor that acts as a regulator of endosomal/membrane trafficking. The protein is able to promote neurite outgrowth in neuronal cultures through activation of the small GTPase Rac1 (Otomo et al., 2003; Topp et al., 2004). Overexpression of ALSin protects cultured motor neuronal cells from mutant SOD1 toxicity suggesting a neuroprotective role. Mutations in *ALSin* may induce a loss of this neuroprotective function (Kanekura et al., 2004). *ALSin* knockout mice do not develop overt motor neuron disease but degeneration of the corticospinal tract has been reported (Cai et al., 2008; Hadano et al., 2006).

### **2.3 ALS3 (18q21)**

Linkage to chromosome 18q21 was identified in a large European family of which 20 members had autosomal-dominant ALS (Hand et al., 2002). This region contains 50 genes but the causal mutation at this locus remains to be identified.

### **2.4 ALS4 (SETX)**

ALS4 is a rare, childhood- or adolescent-onset, autosomal dominant disease, which is also known as distal hereditary motor neuronopathy with pyramidal features. Linkage to chromosome 9q34 was found in a large family from the USA with 49 affected members (Chance et al., 1998). Sequencing of 19 genes in this locus revealed that missense mutations in the senataxin (*SETX*) gene were the cause of ALS4 in several families (Chen et al., 2004). Since then, mutations have been identified in additional ALS patients from China, Italy and the USA (Avemaria et al., 2011; Hirano et al., 2011; Zhao et al., 2009). Interestingly, mutations in *SETX* leading to a premature termination in the protein product have also been identified in ataxia oculomotor apraxia 2 (Moreira et al., 2004).

Genetics of Amyotrophic Lateral Sclerosis 483

siblings (Sapp et al., 2003). This region contains 24 genes but no causal mutation has been

In a large family from Brazil with 28 affected members across 4 generations, linkage was found at chromosome 20q13.3. Sequencing identified a mutation (P56S) in the vesicle associated membrane protein (VAMP)/synaptobrevin-associated membrane protein B (*VAPB*) gene in all affected members of this family (Nishimura et al., 2004). The same mutation was also identified in six additional families with different clinical courses including, ALS8, late-onset spinal muscular atrophy and typical severe ALS with rapid progression. A different mutation (T46I) was detected in a family from the UK (Chen et al.,

The VAPB protein has been implicated in various cellular processes including the formation of the presynaptic terminal in neurons, vesicle trafficking and the unfolded protein response (Chen et al., 2010). Transgenic mice overexpressing ALS mutant VAPB or wild-type VAPB do not develop an overt motor neuron phenotype. However, transgenic mice overexpressing ALS mutant but not wild-type VAPB show TAR DNA-binding protein 43 (TDP-43) positive cytoplasmic inclusions, a pathological hallmark of ALS (Tudor et al., 2010). It has been suggested that mutant VAPB exerts a dominant-negative effect by forming dimeric complexes with wild-type VAPB thereby recruiting it into aggregates (Teuling et al.,

Angiogenin (*ANG*) was identified as a candidate gene for ALS because it is located 237kb downstream of apurinic endonuclease, multifunctional DNA repair enzyme (*APEX*) and because of its functional similarity to vascular endothelial growth factor (VEGF) (Greenway et al., 2004). Both *APEX* and *VEGF* are candidate genes for sALS and will be discussed in the next section. A single nucleotide polymorphism (SNP) in *ANG* was associated with ALS in patients from Ireland and Scotland (Greenway et al., 2004). Missense mutations in *ANG* were found in 4 fALS cases and 11 sALS cases (Greenway et al., 2006). Subsequent sequencing in populations from Europe and the USA identified additional mutations in approximately 2% of fALS cases and 1% of sALS cases (Conforti et al., 2008; Fernández-Santiago et al., 2009; Gellera et al., 2008; Paubel et al., 2008; Wu et al., 2007). However, *ANG* mutations have also been observed in healthy controls suggesting that not all mutations are pathogenic (Corrado et al., 2007). A K17I mutation was identified in a 4-generation family of which one patient presented with ALS, FTD, and Parkinsonism (Van Es et al., 2009a). An obligate carrier did not develop the disease suggesting incomplete penetrance. Two *ANG* mutations (K17I and K54E) were identified in two fALS cases from France who also had a mutation in FUS (Millecamps et al., 2010). An R145C mutation has been observed in a sALS patient with a G93D SOD1 mutation (Luigetti et al., 2011). A recent study showed a significantly higher frequency of *ANG* variants in both ALS and Parkinson's disease (PD) patients which could reflect a genetic susceptibility to widespread neurodegeneration (Van

The ANG protein is a member of the pancreatic ribonuclease superfamily and a potent mediator of new blood vessel formation. In endothelial cells, the protein can promote ribosomal RNA (rRNA) production and cellular proliferation and is able to cleave transfer

identified.

2010).

2007).

**2.9 ALS9 (ANG)** 

Es et al., 2011).

**2.8 ALS8 (VAPB)** 

Senataxin contains a seven-motif domain characteristic for DNA/RNA helicases. It displays strong homology to several genes involved in RNA processing such as the immunoglobulin mu binding protein 2 gene (*IGHMBP2*), in which mutations are known to cause spinal muscular atrophy with respiratory distress type 1 (Grohmann et al., 2001). SETX was shown to be involved in the termination of RNA transcription (Skourti-Stathaki et al., 2011). It is therefore possible that mutations in *SETX* cause neuronal degeneration due to aberrant RNA processing. Overexpression of wild-type senataxin in primary hippocampal neurons is sufficient to trigger neuronal differentiation by protecting cells from apoptosis and promoting neuritogenesis (Vantaggiato et al., 2011).

### **2.5 ALS5 (SPG11)**

This is the most common form of recessive fALS and is characterized by a juvenile onset. In seven families from Tunisia, Pakistan, and Germany, linkage to chromosome 15q15-21 was found (Hentati et al., 1998). Recently, 12 mutations in the spatacsin (*SPG11*) gene were identified in 10 unrelated pedigrees from Italy, Brazil, Canada, Turkey, and Japan (Orlacchio et al., 2010). Ten out of 12 mutations are frameshift or nonsense mutations. Mutations in *SPG11* are known to cause autosomal recessive hereditary spastic paraplegia with a thin corpus callosum (Stevanin et al., 2007).

Spatacsin contains four putative transmembrane domains, a leucine zipper and a coiled-coil domain. The exact function of spatacsin is unknown although it may play a role in axonal transport (Salinas et al., 2008).

### **2.6 ALS6 (FUS)**

Linkage to a 42-Mb region containing more than 400 genes on chromosome 16 was reported in several families (Sapp et al. 2003). Recently, mutations in the fused in sarcoma/translated in liposarcoma (*FUS/TLS*) gene were shown to cause ALS6 (Kwiatkowski et al., 2009; Vance et al., 2009). Several subsequent studies have identified additional mutations in *FUS* in ALS cohorts from different populations with an overall frequency of ~4% in fALS and ~1% in sALS (Belzil et al., 2009; Corrado et al., 2010; Hewitt et al., 2010; Groen et al., 2010). *FUS* mutations have also been detected in fALS patients with frontemporal dementia (FTD) and patients with juvenile ALS with basophilic inclusions (Bäumer et al., 2010; Huang et al. 2010; Yan et al., 2010).

The *FUS* gene encodes for a DNA/RNA binding protein that is involved in several cellular pathways including the splicing, transport and maturation of RNA (Lagier-Tourenne et al., 2010). FUS positive ubiquitinated cytoplasmic inclusions have been observed in spinal cord tissue of sALS and fALS patients without *SOD1* and *FUS* mutations (Deng et al., 2010). The majority of *FUS* mutations identified reside in its C-terminal nuclear localization signal which results in an abnormal cytoplasmic localization of FUS and localization to stress granules (Bosco et al., 2010; Dormann et al., 2010; Ito et al., 2010). In yeast, overexpression of human FUS leads to toxicity, cytoplasmic inclusions and FUS localization to stress granules as can be seen in ALS patients (Ju et al., 2011; Sun et al., 2011). In addition, transgenic rats overexpressing ALS mutant FUS develop progressive paralysis due to motor axon degeneration as well as neuronal loss in the cortex and hippocampus which are phenotypes seen in ALS and FTD (Huang et al., 2011).

#### **2.7 ALS7 (20p)**

Linkage to chromosome 20p was found in a large autosomal dominant fALS pedigree from the USA. A 5-Mb segment was identified that was shared between two affected siblings (Sapp et al., 2003). This region contains 24 genes but no causal mutation has been identified.

### **2.8 ALS8 (VAPB)**

482 Amyotrophic Lateral Sclerosis

Senataxin contains a seven-motif domain characteristic for DNA/RNA helicases. It displays strong homology to several genes involved in RNA processing such as the immunoglobulin mu binding protein 2 gene (*IGHMBP2*), in which mutations are known to cause spinal muscular atrophy with respiratory distress type 1 (Grohmann et al., 2001). SETX was shown to be involved in the termination of RNA transcription (Skourti-Stathaki et al., 2011). It is therefore possible that mutations in *SETX* cause neuronal degeneration due to aberrant RNA processing. Overexpression of wild-type senataxin in primary hippocampal neurons is sufficient to trigger neuronal differentiation by protecting cells from apoptosis and

This is the most common form of recessive fALS and is characterized by a juvenile onset. In seven families from Tunisia, Pakistan, and Germany, linkage to chromosome 15q15-21 was found (Hentati et al., 1998). Recently, 12 mutations in the spatacsin (*SPG11*) gene were identified in 10 unrelated pedigrees from Italy, Brazil, Canada, Turkey, and Japan (Orlacchio et al., 2010). Ten out of 12 mutations are frameshift or nonsense mutations. Mutations in *SPG11* are known to cause autosomal recessive hereditary spastic paraplegia with a thin

Spatacsin contains four putative transmembrane domains, a leucine zipper and a coiled-coil domain. The exact function of spatacsin is unknown although it may play a role in axonal

Linkage to a 42-Mb region containing more than 400 genes on chromosome 16 was reported in several families (Sapp et al. 2003). Recently, mutations in the fused in sarcoma/translated in liposarcoma (*FUS/TLS*) gene were shown to cause ALS6 (Kwiatkowski et al., 2009; Vance et al., 2009). Several subsequent studies have identified additional mutations in *FUS* in ALS cohorts from different populations with an overall frequency of ~4% in fALS and ~1% in sALS (Belzil et al., 2009; Corrado et al., 2010; Hewitt et al., 2010; Groen et al., 2010). *FUS* mutations have also been detected in fALS patients with frontemporal dementia (FTD) and patients with juvenile

ALS with basophilic inclusions (Bäumer et al., 2010; Huang et al. 2010; Yan et al., 2010).

The *FUS* gene encodes for a DNA/RNA binding protein that is involved in several cellular pathways including the splicing, transport and maturation of RNA (Lagier-Tourenne et al., 2010). FUS positive ubiquitinated cytoplasmic inclusions have been observed in spinal cord tissue of sALS and fALS patients without *SOD1* and *FUS* mutations (Deng et al., 2010). The majority of *FUS* mutations identified reside in its C-terminal nuclear localization signal which results in an abnormal cytoplasmic localization of FUS and localization to stress granules (Bosco et al., 2010; Dormann et al., 2010; Ito et al., 2010). In yeast, overexpression of human FUS leads to toxicity, cytoplasmic inclusions and FUS localization to stress granules as can be seen in ALS patients (Ju et al., 2011; Sun et al., 2011). In addition, transgenic rats overexpressing ALS mutant FUS develop progressive paralysis due to motor axon degeneration as well as neuronal loss in the cortex and hippocampus which are phenotypes seen in ALS and FTD (Huang et al., 2011).

Linkage to chromosome 20p was found in a large autosomal dominant fALS pedigree from the USA. A 5-Mb segment was identified that was shared between two affected

promoting neuritogenesis (Vantaggiato et al., 2011).

corpus callosum (Stevanin et al., 2007).

transport (Salinas et al., 2008).

**2.6 ALS6 (FUS)** 

**2.7 ALS7 (20p)** 

**2.5 ALS5 (SPG11)** 

In a large family from Brazil with 28 affected members across 4 generations, linkage was found at chromosome 20q13.3. Sequencing identified a mutation (P56S) in the vesicle associated membrane protein (VAMP)/synaptobrevin-associated membrane protein B (*VAPB*) gene in all affected members of this family (Nishimura et al., 2004). The same mutation was also identified in six additional families with different clinical courses including, ALS8, late-onset spinal muscular atrophy and typical severe ALS with rapid progression. A different mutation (T46I) was detected in a family from the UK (Chen et al., 2010).

The VAPB protein has been implicated in various cellular processes including the formation of the presynaptic terminal in neurons, vesicle trafficking and the unfolded protein response (Chen et al., 2010). Transgenic mice overexpressing ALS mutant VAPB or wild-type VAPB do not develop an overt motor neuron phenotype. However, transgenic mice overexpressing ALS mutant but not wild-type VAPB show TAR DNA-binding protein 43 (TDP-43) positive cytoplasmic inclusions, a pathological hallmark of ALS (Tudor et al., 2010). It has been suggested that mutant VAPB exerts a dominant-negative effect by forming dimeric complexes with wild-type VAPB thereby recruiting it into aggregates (Teuling et al., 2007).

### **2.9 ALS9 (ANG)**

Angiogenin (*ANG*) was identified as a candidate gene for ALS because it is located 237kb downstream of apurinic endonuclease, multifunctional DNA repair enzyme (*APEX*) and because of its functional similarity to vascular endothelial growth factor (VEGF) (Greenway et al., 2004). Both *APEX* and *VEGF* are candidate genes for sALS and will be discussed in the next section. A single nucleotide polymorphism (SNP) in *ANG* was associated with ALS in patients from Ireland and Scotland (Greenway et al., 2004). Missense mutations in *ANG* were found in 4 fALS cases and 11 sALS cases (Greenway et al., 2006). Subsequent sequencing in populations from Europe and the USA identified additional mutations in approximately 2% of fALS cases and 1% of sALS cases (Conforti et al., 2008; Fernández-Santiago et al., 2009; Gellera et al., 2008; Paubel et al., 2008; Wu et al., 2007). However, *ANG* mutations have also been observed in healthy controls suggesting that not all mutations are pathogenic (Corrado et al., 2007). A K17I mutation was identified in a 4-generation family of which one patient presented with ALS, FTD, and Parkinsonism (Van Es et al., 2009a). An obligate carrier did not develop the disease suggesting incomplete penetrance. Two *ANG* mutations (K17I and K54E) were identified in two fALS cases from France who also had a mutation in FUS (Millecamps et al., 2010). An R145C mutation has been observed in a sALS patient with a G93D SOD1 mutation (Luigetti et al., 2011). A recent study showed a significantly higher frequency of *ANG* variants in both ALS and Parkinson's disease (PD) patients which could reflect a genetic susceptibility to widespread neurodegeneration (Van Es et al., 2011).

The ANG protein is a member of the pancreatic ribonuclease superfamily and a potent mediator of new blood vessel formation. In endothelial cells, the protein can promote ribosomal RNA (rRNA) production and cellular proliferation and is able to cleave transfer

Genetics of Amyotrophic Lateral Sclerosis 485

17 genes in this region revealed a homozygous deletion in the gene for optineurin (*OPTN*), a gene known to cause primary open-angle glaucoma, in two siblings and an individual from a different family (Murayama et al., 2010; Rezaie et al., 2002). In addition, a homozygous nonsense (Q398X) mutation was identified in one fALS case (Murayama et al., 2010). Subsequent screening in a larger cohort of fALS and sALS patients identified a heterozygous missense mutation (E478G) in a four individuals with ALS from two families (Murayama et al., 2010). A homozygous E478G mutation was identified in a Japanese fALS case in a different study (Iida et al., 2011). One additional nonsense mutation and one missense mutation in *OPTN* were identified in fALS cases from Italy (Del Bo et al., 2011). Two separate studies identified novel variants in fALS patients but the authors state that these variants may be a genetic predisposition to glaucoma instead of causing ALS (Belzil et al., 2011; Millecamps et al., 2011). One study also detected mutations in sALS patients with a rapid disease progression (van Blitterswijk et al., 2011). Another study could not identify

OPTN is a multifunctional protein involved in membrane trafficking, maintainance of the Golgi complex, and exocytosis (Sahlender et al., 2005). OPTN can inhibit the activation of NFκB and it has been proposed that mutations in *OPTN* causing ALS may relieve this

Recently an exome sequencing study detected a mutation in the gene encoding valosincontaining protein (*VCP*) in an Italian family. Subsequent screening in 210 ALS cases from unrelated families identified four mutations in *VCP* in four different families from Italy and the USA (Johnson et al., 2010). Mutations in the gene for *VCP*, located on chromosome 9p13.3, are a known cause for the multi-system degenerative disease inclusion body myopathy with Paget's disease and frontotemporal dementia (IBMPFD) (Watts et al. 2004). IBMPFD, like ALS, is characterized pathologically by TDP-43 inclusions (Weihl et al., 2008). VCP is an AAA+-ATPase that mediates ubiquitin-dependent extraction of substrates from multiprotein complexes for subsequent recycling or degradation by the proteasome. It plays a role in a variety of cellular functions including Golgi biogenesis, cell cycle regulation, DNA damage repair and protein homeostasis through the ubiquitin-proteasome system (Ju and Weihl, 2010). It is thought that *VCP* mutations result in the impairment of protein degradation trough both the ubiquitin-proteasome system and autophagy leading to the formation of inclusions. *VCP* mutations found in FTD and ALS have been shown to disrupt TDP-43 localization from the nucleus to the cytoplasm which could be caused by the disruption in protein homeostasis (Gitcho et al, 2009a; Ju and Weihl, 2010). In mice, a missense mutation in vacuolar sorting protein 54, the mouse homologue of VCP, causes

In addition to the genes listed in the previous sections, several other genes have been

Dynactin 1 (*DCTN1*) was discovered as a candidate gene for ALS when a G59S mutation in this gene was identified in a family with a slowly progressive, autosomal dominant form of lower motor neuron disease without sensory symptoms (Puls et al., 2003; Puls et al., 2005). Subsequent sequencing of the *DCNT1* gene in 250 ALS patients revealed the presence of

*OPTN* mutations in fALS and sALS patients (Sugihara et al., 2011).

inhibition and cause neuronal death (Murayama et al., 2010).

motor neuron degeneration (Schmitt-John et al., 2005).

**2.14 Other fALS associated genes** 

implicated in fALS.

**2.13 ALS14 (VCP)** 

RNA which results in inhibition of protein translation (Yamasaki et al., 2009). ANG is also expressed in spinal motor neurons (Sebastià et al., 2009). It is thought that *ANG* mutations cause ALS due to a loss of function and it has been shown that wild-type but not mutant angiogenin is neuroprotective and that mutant angiogenin impairs neurite outgrowth *in vitro* (Sebastià et al., 2009; Subramanian et al., 2008; Wu et al., 2007).
