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Defective axonal motility of a unique Huntingtin‐Rab4 vesicle causes synaptic defects and behavioral deficits seen in Huntington’s disease
Author(s) -
Gunawardena Shermali
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.042096
Subject(s) - huntingtin , biology , synaptic vesicle , neuroscience , synaptotagmin 1 , synaptic vesicle recycling , microbiology and biotechnology , motility , batten disease , axoplasmic transport , huntington's disease , population , vesicle , genetics , pathology , disease , medicine , membrane , environmental health , gene , mutant
Background Huntington’s disease (HD) is a progressive neurodegenerative disease characterized by expansion in the polyQ region of Huntingtin (HTT). HTT is ubiquitous but the native function of HTT remains elusive. HTT is required for neuron survival and viability, as loss of HTT causes early embryonic lethality. Although HTT has been implicated to have numerous binding partners involved in a wide array of cellular processes, the significance of these interactions in neurons remain allusive. HTT moves bi‐directionally within axons. However, the specific vesicle types that HTT is present on and the cargoes that HTT‐containing vesicles carry to/from synapses are unknown. Here we test the hypothesis that HTT is involved in the motility of Rab4 whose function remains ambiguous. Methods Simultaneous dual‐view imaging and computational analysis coupled with Drosophila genetics is used to isolate moving HTT‐Rab4 vesicles in vivo . Findings are validated in mouse brains and in neurons differentiated from iPSCs from WT and HD individuals. Results We found that a sub‐population of moving Rab4‐containing vesicles contained HTT. Reduction of HTT disrupts the bi‐directional motility of Rab4, prompting axonal and synaptic accumulations. Simultaneous dual‐color in vivo imaging revealed that HTT and Rab4 are present on a unique class of vesicles that contain synaptotagmin, synaptobrevin, and/or Rab11, but not APP or Rab3. The HTT‐Rab4 vesicle uses kinesin‐1 and dynein for its bi‐directional movement within axons and is aided by HTT‐interacting protein HIP1 and Rab‐interacting protein Rip11/Rab11‐FIP5, but not HAP1. While pathogenic HTT disrupts Rab4 motility causing larval locomotion defects, synaptic morphological defects and decreased adult lifespan, expression of Rab4 rescues these pathogenic phenotypes. Consistent with these observations, Rab4 motility was perturbed in human neurons derived from HD patient iPSCs, likely due to disrupted associations between the polyQHTT‐Rab4 vesicle and motor proteins. Conclusions Our observations propose a model in which HTT links unique Rab4 vesicles to motors for their motility to synapses. Pathogenic HTT perturbs the axonal transport of the HTT‐Rab4 vesicle causing synaptic and behavioral defects. The rescue of these pathogenic defects by excess Rab4 highlight a potential novel therapeutic target for early intervention prior to neuronal loss and behavioral defects observed in HD.