KIF1A neurodegenerative disease mutations modulate motor motility and force generation

KIF1A is involved in fast axonal transport of synaptic vesicle precursor, neurofilament, and dense-core vesicle, essential for neuronal development and maintenance. Several point mutations in the KIF1A motor domain have been identified in patients with various motor neuron diseases. Recent studies have shown that these mutations affected the motor and cargo localization in cultured hippocampal and C.elegans neurons. However, a detailed analysis of these mutations on KIF1A motility, force generation, and cargo transport is largely unexplored. Here, we have analyzed the effect of 16 point mutations and showed that these mutations significantly decreased the motor velocity and landing rates compared to wild-type motors. Except for A255V, mutations V144F, V220I, and E233D mildly affected motor mechanical outputs. S58L, A202P, R216P, R216H, L249Q, T312M, and R316W mutants exhibited drastic impairments in the motility properties, force generation, and cargo transport. Notably, T46M, T99M, G102D, S215R, and E253K mutants showed strong microtubule binding, resulting in complete disruption of cargo transport. Our study provides the first comprehensive demonstration of KIF1A disease mutations at the molecular level. The observed changes in motility properties and cargo transport align with the severity of disease phenotype observed in KIF1A-associated neurological disorders)