Novel Kinesin Family 1A Variants Linked to Atypical Parkinsonism Elicit Altered Neuronal TDP-43 Interactions and Dendritic Atrophy.

Abstract

Analysis of iPSC-derived neurons from the son of a father-son pair with novel familial Variants of Uncertain Significance in KIF1A [c.408C>G (p.Asp136Glu); c.3914G>A (p.Arg1305His)] reveal pathological features of altered TDP-43 localization, interactions and stunted dendritic arbors. Both patients developed spasticity and parkinsonism in their mid-60s, with the father dying at age 71. There was impaired putamenal dopamine uptake with preserved uptake in the caudate nuclei, and decreased anisotropy by tractography in multiple motor pathways. Given shared transcriptional mechanisms of hindbrain and spinal cord developmental patterning among neurons of the motor circuitry, iPSC-derived motor neurons from fibroblasts donated by the son were created to investigate the impact of KIF1A mutations on TDP-43 subcellular localization, biochemical interactions of endogenous wildtype- and mutant-KIF1A and endogenous TDP-43, and the pathological impact of these KIF1A variants on dendritic arborization using Sholl analysis. Neuropathological assessment of the father, who shared the same KIF1A variants, revealed tauopathy and TDP-43 proteinopathy throughout the brainstem. Quantitative imaging of patient iPSC neurons identified TDP-43 mislocalization to the soma and dendritic atrophy. The KIF1A variant also elicited decreased biochemical interactions of both itself and TDP-43 with a spectrum of known TDP-43-associated proteins. These data suggest that this novel KIF1A mutant mediates altered TDP-43 interactions, stunting of the synaptic architecture, and clinical phenotypes coincident with neurodegenerative movement disorders.