The genetics of amyotrophic lateral sclerosis

Abstract

Purpose of review: Amyotrophic lateral sclerosis (ALS) has a strong genetic basis, but the genetic landscape of ALS appears to be complex. The purpose of this article is to review recent developments in the genetics of ALS.

Recent findings: Large-scale genetic studies have uncovered more than 40 genes contributing to ALS susceptibility. Both rare variants with variable effect size and more common variants with small effect size have been identified. The most common ALS genes are C9orf72 , SOD1 , TARDBP and FUS . Some of the causative genes of ALS are shared with frontotemporal dementia, confirming the molecular link between both diseases. Access to diagnostic gene testing for ALS has to improve, as effective gene silencing therapies for some genetic subtypes of ALS are emerging, but there is no consensus about which genes to test for.

Summary: Our knowledge about the genetic basis of ALS has improved and the first effective gene silencing therapies for specific genetic subtypes of ALS are underway. These therapeutic advances underline the need for better access to gene testing for people with ALS. Further research is needed to further map the genetic heterogeneity of ALS and to establish the best strategy for gene testing in a clinical setting.

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FIGURE 1

Overview of most important ALS-related genes and their roles in motor neurons. (a) NEK1 and C21orf2 play a role in ciliogenesis and cilia maintenance. (b) VCP, TBK1, C9orf72, UBQLN1, SQSTM1, VAPB, CHMP2B, ANXA11, SIGMAR1, OPTN, FIG4, ALS2 and CCNF are involved in the proteasomal and/or autophagy-mediated degradation of misfolded proteins. (c) CHCHD10, SOD1 and TDP-43 are involved in the regulation of mitochondrial dynamics. (d) FUS, TDP-43, NEK1 and C21orf2 facilitate DNA repair. (e) TDP-43, FUS, ANG, SETX, HNRNPA1/A2B1, MATR3, ATXN2 and TIA-1 regulate the RNA metabolism of motor neurons at various levels. (f) ALS2, PFN1, NEFH, PRPH, TUBA4A, SPG11 and NEK1 contribute to the assembly and/or stability of cytoskeletal components. KIF5A and DCTN1 are key players in bidirectional axonal transport. Hh, hedgehog; SMO, Smoothened receptor; UPS, ubiquitin-proteasome system; SG, stress granule; pri-miRNA, primary microRNA; premiRNA, precursor microRNA. Figure created with BioRender.com.