Amyotrophic lateral sclerosis: translating genetic discoveries into therapies

Abstract

Recent advances in sequencing technologies and collaborative efforts have led to substantial progress in identifying the genetic causes of amyotrophic lateral sclerosis (ALS). This momentum has, in turn, fostered the development of putative molecular therapies. In this Review, we outline the current genetic knowledge, emphasizing recent discoveries and emerging concepts such as the implication of distinct types of mutation, variability in mutated genes in diverse genetic ancestries and gene-environment interactions. We also propose a high-level model to synthesize the interdependent effects of genetics, environmental and lifestyle factors, and ageing into a unified theory of ALS. Furthermore, we summarize the current status of therapies developed on the basis of genetic knowledge established for ALS over the past 30 years, and we discuss how developing treatments for ALS will advance our understanding of targeting other neurological diseases.

Fig. 1 |. Proportion of familial and sporadic ALS cases attributed to mutations in the corresponding disease-causing genes.

Mutations in the known amyotrophic lateral sclerosis (ALS) genes explain approximately 76% of familial and 25% of sporadic ALS. The four most common ALS-associated genes, C9orf72, SOD1, TARDBP and FUS comprise 60% of familial and 11% of sporadic ALS. The proportion attributed to recently identified or rarely implicated genes has not been established.

Fig. 2 |. Thirty years of gene discovery in ALS and FTD.

The first Mendelian gene for amyotrophic lateral sclerosis (ALS) was identified in 1993 (ref. 19), and the first genome-wide association study (GWAS) for ALS was published in 2007 (ref. 103). Further GWAS and gene hunting studies identified several significant loci (P < 5 × 10⁻⁸) and genes associated with ALS, frontotemporal dementia (FTD) or ALS/FTD. Summary-level associations were extracted from the EBI-GWAS website.

Fig. 3 |. Frequency of causal mutations in the four most common ALS genes in diverse populations.

The incidence of amyotrophic lateral sclerosis (ALS) varies in distinct populations. Although the C9orf72 repeat expansion is rare in Asia, it is the most frequent cause of ALS in Scandinavian populations. Similarly, a founder mutation in TARDBP explains approximately 35% of the disease in Sardinia.The frequency of familial cases explained by the mutated genes in different geographical regions is obtained from references^,,; the regions are North America (Canada and USA); Europe (Italy, Germany, Spain, Switzerland, France, Belgium, UK, Netherlands and Slovenia); Sardinia; Scandinavia (Sweden and Finland); Asia (Japan, Korea, China, India and Iran); and Australia.

Fig. 4 |. A model of ALS that integrates genetics, environment and ageing.

Amyotrophic lateral sclerosis (ALS) may occur owing to multiple overlapping factors, including a primary disease-causing mutation, a genetic predisposition that influences disease manifestation, environmental and lifestyle factors, and ageing. Together, they comprise a multifaceted, complex system, in which the integrity of each element is vital to maintain the integrity of the motor neurons.