Mechanisms of Neurodegeneration in KIF5A ALS/FTD

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurogenerative disease characterized by progressive dysfunction and death of motor neurons. Patients with ALS develop neuromuscular weakness leading to respiratory failure and fatality within five years from onset. Many ALS patients also develop Frontotemporal Dementia (FTD) leading to progressive personality change and language deficit (ALS/FTD). The underlying causes of neurodegeneration in ALS and FTD are poorly understood but recently a number of disease causative mutations have been defined with significant clinicopathologic overlap suggesting a shared mechanism. In 2018, mutations were identified in ALS patients in KIF5A, which is a neuron-specific subunit of the anterograde motor protein Kinesin-1. Subsequent studies identified mutations in KIF5A in patients with ALS/FTD providing a new link between KIF5A dysfunction and dementia. Kinesin-1 functions in axonal transport and cytoskeletal dynamics but the factors underlying the selective vulnerability of various neuronal populations to mutations in disease have not been clearly defined. Thus, further characterization of the pathogenic mechanisms of Kinesin-1 mutations has potential to advance knowledge of motor protein function in neuronal homeostasis. We will define the consequences of KIF5A∆Exon27 mutation on the assembly and motility of KIF5A motor/cargo complexes, and Elucidate the effects of KIF5A∆Exon27 mutation on the structure and maintenance of the neuronal cytoskeleton.