Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder clinically characterized by rapidly progressive muscle weakness and death due to respiratory failure, typically within 2 to 4 years of symptom onset.
Although ALS is perceived as being rare, approximately 6,000 Americans die annually from the condition. Furthermore, the number of ALS cases across the globe is predicted to increase to nearly 400,000 by 2040, predominantly due to aging of the population.
Approximately 10% of ALS cases display a family history (FALS), whereas the remaining 90% of ALS cases are sporadic (SALS) in nature.
Driven in large part by advances in genotyping and sequencing technology, the genetic etiology of two-thirds of FALS cases and about 10% of SALS cases is now known. Mutations in SOD1 were the first identified cause of ALS, contributing to ~20% of FALS and ~2% of SALS. More recently, pathogenic hexanucleotide repeat expansions located within the first intron of the C9orf72 gene on chromosome 9p21 were identified as the most common cause of both FALS (~40%) and SALS (~7%). This repeat expansion contributes to ~10% of all frontotemporal dementia (FTD) cases, thus genetically explaining much of the overlap between these clinical syndromes. As a result of these major discoveries, there are several ongoing efforts toward directed silencing of these mutant genes, which could result in a therapeutic treatment for up to 10% of all ALS cases and for a similar portion of FTD cases.
To identify novel genes associated with ALS, this study undertook two lines of investigation:
Researchers carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Researchers also performed a rare variant burden analysis comparing 1,138 familial ALS cases and 19,494 controls. Through both approaches, this study identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS.
Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases.
In addition to the insights provided by each novel ALS gene, the collective knowledge gained from genetic factors provides a more comprehensive understanding of the interacting pathways underlying motor neuron degeneration. For example, the identification of ALS genes has revealed at least three pathways believed to contribute to the development of ALS: (1) RNA metabolism (based on the observation of mutations in C9orf72, TDP-43, FUS, HNRNPA1, and MATR3), (2) protein homeostasis (UBQLN2, VCP, OPTN, and VAPB), and (3) cytoskeletal dynamics (PFN1, TUBA4A, and DCTN1).
Taken together, these results broaden the phenotypic spectrum resulting from mutations in KIF5A and reinforce the role of cytoskeletal defects in the pathogenesis of ALS. Understanding the mechanisms leading to disease pathogenesis provides novel targets for therapeutic intervention that may be applicable to all forms of ALS.
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