ALS Genetics, Mechanisms, and Therapeutics: Where Are We Now?

Abstract

The scientific landscape surrounding amyotrophic lateral sclerosis (ALS) continues to shift as the number of genes associated with the disease risk and pathogenesis, and the cellular processes involved, continues to grow. Despite decades of intense research and over 50 potentially causative or disease-modifying genes identified, etiology remains unexplained and treatment options remain limited for the majority of ALS patients. Various factors have contributed to the slow progress in understanding and developing therapeutics for this disease. Here, we review the genetic basis of ALS, highlighting factors that have contributed to the elusiveness of genetic heritability. The most commonly mutated ALS-linked genes are reviewed with an emphasis on disease-causing mechanisms. The cellular processes involved in ALS pathogenesis are discussed, with evidence implicating their involvement in ALS summarized. Past and present therapeutic strategies and the benefits and limitations of the model systems available to ALS researchers are discussed with future directions for research that may lead to effective treatment strategies outlined.

Keywords: FUS; TDP-43; amyotrophic lateral sclerosis; cell models; disease mechanisms; missing heritability; therapeutics.

FIGURE 1

Proportion of ALS explained by the four most commonly mutated genes in Asian and European populations. Data adapted from Zou et al. (2017).

FIGURE 2

(A) Domain structure of TDP-43. Numbers refer to amino acid positions. NLS is nuclear localization signal, NES is nuclear export signal, RRM1 and RRM2 are RNA recognition motifs. Prion-like protein (PLP) domain spans from amino acids 274–414. ALS associated mutations are clustered in the glycine-rich region. (B) Domain structure of the FUS protein. Numbers refer to amino acid positions. NLS is nuclear localization signal, NES is nuclear export signal, RRM is the RNA recognition motif, ZnF is the Zinc-Finger domain. Prion-like protein domains span from amino acids 1–239 and 391–407. A cluster or ALS associated mutations occur within the nuclear localization signal with others spread throughout the gene.

FIGURE 3

Schematic of TDP-43 autoregulation and misregulation in ALS. When in nuclear excess, TDP-43 binds to a region in the 3′UTR of the TARDBP pre-mRNA leading to alternative polyadenylation and splicing; this produces mature mRNA transcripts that are subject to nonsense mediated decay. Nuclear depletion of TDP-43 as seen in ALS (right) leads to continuous upregulation of TDP-43 synthesis as more of the translated isoforms are produced.

FIGURE 4

Proposed pathogenic mechanisms and pathology in ALS. (1) Nucleocytoplasmic transport defects including altered transport of RNA molecules and RNA-binding proteins. (2) Altered RNA metabolism. RNA-binding proteins including TDP-43 or FUS may become mislocalized in the cytoplasm leading to altered transcription and splicing. Stress granule dynamics are also affected. (3) Proteostasis is impaired with aggregating proteins including TDP-43 accumulating in the cytoplasm. There is evidence that the two main protein clearance pathways, autophagy and the UPS may be involved. (4) Impaired DNA repair: several ALS-linked genes including FUS, TARDBP, TAF15, SETX, and EWSR1 are involved in DNA repair. (5) Mitochondrial dysfunction resulting in the increased formation of reactive oxygen species (ROS) has been proposed as an initiating factor in ALS. Several ALS-linked proteins including SOD1, TDP-43, and FUS interact with mitochondria. (6) Axonal transport defects have been implicated in ALS pathogenesis. Neuropathological evidence has shown evidence of this including neurofilament accumulation and cytoskeletal disorganization. (7) Several ALS-linked genes including OPTN, VAPB, CHMP2B, and UNC13A are involved in vesicular transport. Impaired vesicular trafficking can lead to protein accumulation and golgi fragmentation which has been observed in ALS patients. (8) Neuroinflammation: the secretion of inflammatory proteins by activated microglia leads to the potentially neurotoxic activation of astrocytes, which may contribute to the death of neurons and oligodendrocytes. (9) Excitotoxicity: glutamate receptor overstimulation has been proposed to occur via several mechanisms including increased synaptic glutamate release, alterations to AMPA receptors and reduced clearance of glutamate by astrocytes. (10) Oligodendrocyte dysfunction may lead to reduced support for neurons. Changes in lactate production and transport via MCT1 have been implicated.