Skip to main content
Open Access Publications from the University of California


UC San Francisco Electronic Theses and Dissertations bannerUCSF

Disease-Associated Mutations in Human BICD2 Hyperactivate Motility of Dynein-Dynactin


Mammalian cytoplasmic dynein is a microtubule-based motor that is involved in many cellular functions, one of which includes the retrograde transport of cargo. In contrast to yeast dynein, which is processive on its own, mammalian dynein requires both an adaptor protein and dynactin in order to achieve micron long run-lengths. Bicaudal D2 (BICD2), a protein comprised of three distinct coiled-coils, is one such adaptor. Recent studies have reported that mutations in BICD2 are associated with neurodegenerative diseases that include spinal muscular atrophy. In this dissertation, I demonstrate through biochemical and single molecule microscopy assays that full-length BICD2 is auto-inhibited and can be activated to interact with dynein and dynactin via the addition of one of its interacting partners, Rab6a. Testing of four BICD2 disease-associated mutations with this same set of assays reveal that, compared to wild-type, the mutants exhibit an increased formation of motile motor complexes. I further confirm this finding by developing an in vitro cargo reconstitution assay using liposomes as proxies for vesicles. This apparent ability to increase transport by the mutants is also observed in cells using an inducible re-localization system with peroxisomes. When overexpressed in rat hippocampal neurons, the BICD2 mutants lead to decreased neurite growth. Altogether, this work shows that dominant mutations in BICD2 hyperactivate dynein-driven motility and suggest that an imbalance of minus versus plus end–directed microtubule motility in neurons may underlie spinal muscular atrophy.

Main Content
For improved accessibility of PDF content, download the file to your device.
Current View