Trabid patient mutations impede the axonal trafficking of adenomatous polyposis coli to disrupt neurite growth

• DOI: 10.7554/elife.90796.3
• Publication Date: 2023-12-15T13:00:43Z
• Authors: Daniel Frank; Maria Bergamasco; Michael J Mlodzia...; Andrew Kueh; Ellen Tsui; Cathrine Hall; Georgios Kastrappis; Anne Kathrin Voss; Catriona McLean; Maree Faux; Kelly L Rogers; Bang Tran; Elizabeth Vincan; David Komander; Grant Dewson; Hoanh Tran
• Keywords: Neurite

ZRANB1 (human Trabid) missense mutations have been identified in children diagnosed with a range of congenital disorders including reduced brain size, but how Trabid regulates neurodevelopment is not understood. We characterized these patient cells and mice to identify key role for the regulation neurite growth. One flanked catalytic cysteine its deubiquitylating (DUB) activity was abrogated. The second variant retained DUB activity, failed bind STRIPAK, large multiprotein assembly implicated cytoskeleton organization neural development. Zranb1 knock-in harboring either exhibited neuronal glial cell densities motor deficit consistent fewer dopaminergic neurons projections. Mechanistically, both DUB-impaired STRIPAK-binding-deficient variants impeded trafficking adenomatous polyposis coli (APC) microtubule plus-ends. Consequently, formation growth cones trajectory outgrowth from mutant midbrain progenitors were severely compromised. propose that STRIPAK recruits deubiquitylate APC, Trabid, APC becomes hyperubiquitylated mislocalized causing impaired underlie developmental phenotypes.