Genetics of Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating, uniformly lethal degenerative disorder of motor neurons that overlaps clinically with frontotemporal dementia (FTD). Investigations of the 10% of ALS cases that are transmitted as dominant traits have revealed numerous gene mutations and variants that either cause these disorders or influence their clinical phenotype. The evolving understanding of the genetic architecture of ALS has illuminated broad themes in the molecular pathophysiology of both familial and sporadic ALS and FTD. These central themes encompass disturbances of protein homeostasis, alterations in the biology of RNA binding proteins, and defects in cytoskeletal dynamics, as well as numerous downstream pathophysiological events. Together, these findings from ALS genetics provide new insight into therapies that target genetically distinct subsets of ALS and FTD.

Figure 1.

The phenotypic spectrum of amyotrophic lateral sclerosis (ALS) genetics. (A) Forty-six ALS-related genes are arrayed along axes that depict two major phenotypic aspects: the extent to which corticospinal versus lower motor neurons are involved (y-axis) and the overlap with frontotemporal dementia (FTD) (x-axis). The diameters of each gene approximate their relative frequencies. (B) The phenotypic overlap of ALS genes with hereditary spastic paraplegia (HSP), frontotemporal dementia (FTD), mitochondrial disease, and lower motor neuropathies (LMN) is shown.

Figure 2.

The common ALS genes define three primary themes in pathophysiology: conformational instability and aggregation of proteins, impaired trafficking of RNA, and altered cytoskeletal dynamics. These converge on multiple secondary, downstream pathologic processes that include activation of endoplasmic reticulum (ER) stress and autophagy, proteasomal dysfunction, altered mitochondrial function, disturbed axonal transport, altered dendritic morphology, and excitotoxicity.

Figure 3.

Protein homeostasis is disturbed in ALS. Many ALS genes highlight loss of protein quality control as a central feature of the disease. Misfolding of proteins may reflect many factors including aberrant folding and quality control at the ER (disturbed ER-associated degradation or ERAD), inherent instability due to mutations, aggregation during residence in stress granules, or imperfect clearance via proteasomes or autophagy. Self-assembly of misfolded proteins may lead to propagated instability and prion-like spreading of pathology.

Figure 4.

Multiple ALS genes indicate disturbances of RNA-binding proteins and RNA synthesis, trafficking, and function. A diversity of pathologies may arise including altered histone acetylation (elongator acetyltransferase complex subunit 3 [ELP3]), disturbed helicase activity (senataxin), altered splicing and synthesis of microRNA (TAR DNA-binding protein [TDP-43], fused in sarcoma [FUS]), deposition of RNA foci and generation of RNA dipeptides (C9orf72), impaired nucleocytoplasmic transport (C9orf72), and formation of aggregates via stress granules (many of the RNA-binding proteins). Axonal movement of RNA granules may be impaired, with secondary alterations in local protein translation in dendrites and neuromuscular junctions.

Figure 5.

Cytoskeletal dynamics are altered in ALS. Mutations in profilin-1 are likely to impair energy-dependent extension of filamentous actin and elongation of growth cones, a process that is enhanced by reduction in signaling from ephrinA4. Tubulin mutations compromise the structures of microtubules. Mutations in dynactin are predicted to impair retrograde transport along the microtubule backbone.