Genetics of ALS
Most ALS cases occur without a clearly identified cause and are therefore referred to as sporadic ALS (SALS). In contrast, a positive family history is present in ∼10% of all patients (familial ALS; FALS) (van Blitterswijk et al., 2012; Nguyen et al., 2018) and these genetic mutations cause ALS in a mostly autosomal-dominant manner (Supplementary Table 1 and Figure 2). However, several recently discovered mutations have been described in patients diagnosed with SALS (Renton et al., 2014; Al Sultan et al., 2016; Taylor et al., 2016). The patterns of selective MN degeneration and vulnerability are similar between FALS and SALS (Comley et al., 2015), implying that shared molecular mechanisms exist between the two conditions.
FIGURE 2  Frequency of mutated genes in FALS patients. The first gene found to harbor mutations causing FALS encodes Cu/Zn superoxide dismutase (SOD1), an enzyme that detoxifies superoxide radicals (Rosen et al., 1993). Mutations in SOD1 account for 12–23.5% of FALS cases, representing 1–2.5% of all ALS, and 186 ALS mutations have now been described1. Since then, mutations in approximatively 26 genes have been identified (Supplementary Table 1 and Figure 2) using genome-wide or exome-wide association studies combined with segregation analysis. Hexanucleotide repeat expansions (GGGGCC) within the first intron of the chromosome 9 open reading frame 72 (C9orf72) gene are the most common cause of FALS and FTD (∼30–50% of FALS, ∼10% of SALS 25% of familial FTD and ∼5% of apparently sporadic ALS and FTD) (DeJesus-Hernandez et al., 2011b; Renton et al., 2011; Majounie et al., 2012; Devenney et al., 2014) (Supplementary Table 1 and Figure 2), in both Europe and North America (DeJesus-Hernandez et al., 2011b; Renton et al., 2011). However, this mutation is much rarer in Asian and Middle Eastern populations (Majounie et al., 2012; Woollacott and Mead, 2014). Healthy individuals possess ≤ 11 GGGGCC repeats in C9orf72 (Rutherford et al., 2012; Harms et al., 2013; van der Zee et al., 2013), whereas hundreds to thousands of repeats are present in ALS/FTD patients (Beck et al., 2013; Harms et al., 2013; van Blitterswijk et al., 2013; Suh et al., 2015). After C9orf72, mutations in SOD1 (20% of FALS), TARDPB encoding TDP-43 (5% of FALS, >50% of FTD) (Rutherford et al., 2008; Sreedharan et al., 2008; Borroni et al., 2010; Kirby et al., 2010), Fused in sarcoma encoding FUS (FUS, 5% of FALS) (Belzil et al., 2009; Blair et al., 2009; Chiò et al., 2009; Kwiatkowski et al., 2009; Neumann et al., 2009; Vance et al., 2009), and CCNF encoding cyclin F (0.6–3.3% of FALS-FTD) are more frequent than the remaining 20 genes mutated in the much rarer forms of FALS (Supplementary Table 1). The physiological functions and properties of the proteins encoded by these genes can be grouped according to their involvement in protein quality control, cytoskeletal dynamics, RNA homeostasis and the DNA damage response. However, it is possible that genetic inheritance could sometimes be missed, due to incomplete penetrance or an oligogenic mode of inheritance, whereby more than one mutated gene is necessary to fully present disease (Nguyen et al., 2018). Consistent with this notion, the frequency of ALS patients carrying two or more mutations in ALS-associated genes is in excess of what would be expected by chance (van Blitterswijk et al., 2012; Veldink, 2017; Zou et al., 2017; Nguyen et al., 2018).
TDP-43 is an ubiquitously expressed RNA-binding protein belonging to the heterogeneous nuclear ribonucleoprotein (hnRNP) family. Fifty three mutations in TARDBP have now been associated with FALS, located within all but one reside of the C-terminal domain of TDP-43 [Gitcho et al., 2008; Kabashi et al., 2008; Van Deerlin et al., 2008; http://alsod.iop.kcl.ac.uk/]. Pathological forms of TDP-43 – phosphorylated, fragmented, aggregated, ubiquitinated TDP-43 – were identified as the major component of MN inclusions (Neumann et al., 2006) in almost all ALS cases, including SALS (97%) (Arai et al., 2006; Neumann et al., 2006; Mackenzie et al., 2007; Scotter et al., 2015; Le et al., 2016). TDP-43 pathology is also observed in C9orf72 mutation cases in several brain regions, including the frontal, temporal and primary motor cortices, hippocampus, basal ganglia, amygdala, thalamus and midbrain (Murray et al., 2011; Hsiung et al., 2012; Mahoney et al., 2012; Irwin et al., 2013; Mackenzie et al., 2013; Balendra and Isaacs, 2018), highlighting an important role for TDP-43 in neurodegeneration in both SALS and FALS. Moreover, ALS and FTD cases bearing TDP-43 pathology are often referred to “TDP-43 proteinopathies” (Mackenzie et al., 2009). TDP-43 shares similar functional roles in RNA-binding, splicing and nucleocytosolic RNA transport as FUS. Fifty nine mutations in FUS have been identified in both SALS and FALS patients (Lattante et al., 2013; http://alsod.iop.kcl.ac.uk/) and FUS colocalises with TDP-43 in protein aggregates in MNs of a proportion of SALS and FALS patients (Kwiatkowski et al., 2009; Deng et al., 2010).