Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective death of upper and lower motor neurons (MN), leading to weakness and eventually death by respiratory failure. There is no effective treatment, however recent advances in the genetics of ALS, and to the success of gene therapy in the motor neuron disease spinal muscular atrophy has resulted in increasing optimism that, for certain genetic forms of ALS, there may so be hope for meaningful disease modifying therapies. Whole genome/exome sequencing and genome-wide association studies (GWAS) recently revealed that ALS-associated single nucleotide variants are located in the C-terminal domain of the kinesin KIF5A. KIF5A is a neuron-specific cytoskeletal motor protein responsible for the anterograde axonal transport of diverse proteins, ribonucleoproteins and cellular organelle cargos such as mitochondria. The protein is composed of three functional domains; 1) an N-terminal/coiled- coiled motor domain responsible for microtubule binding and movement, 2) a central ?stalk? domain, and 3) a C-terminal/cargo binding domain. Remarkably, missense mutations in the N-terminal region had been previously reported in people with hereditary spastic paraparesis (HSP), many with features of hereditary axonal motor neuropathy (CMT2). These N-terminal mutations appear to result in a loss of the kinesin function that would be predicted to affect all cargos of KIF5A. In this project, we will to characterize a new ALS mouse model linked to a mutation in the cargo-binding domain of KIF5A gene. We have created a novel mouse model of ALS by introducing a splice site variant (c.3005+1G>A) in the mouse Kif5a gene that is the homolog to the recently reported human c.3020+1G>A KIF5A mutation associated with ALS using CRISPR/Cas9. Here, we propose a comprehensive behavioral, electrophysiological and pathological characterization of this mouse model as a first step to understand the functional consequences of KIF5A ALS-associated mutations and to create a tool for future preclinical and basic science studies.
Amyotrophic lateral sclerosis (ALS) is a brutal, fatal neurodegenerative disease that poses a significant health problem and impact on society. Recent advances in the genetics of ALS have presented new opportunities to understand the cause of ALS. The current study will characterize a novel mouse model of ALS that we have created to understand how recently discovered mutations in the KIF5A gene cause ALS. This model will be a tool for us and other investigators to ultimately design new approaches to treat ALS.
