Axon guidance pathways modulate neurotoxicity of ALS-associated UBQLN2

Abstract: Mutations in the ubiquitin (Ub) chaperoneUbiquilin 2 (UBQLN2)cause X-linked forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) through unknown mechanisms. Here we show that aggregation-prone, ALS-associated mutants of UBQLN2 (UBQLN2^ALS) trigger heat stress-dependent neurodegeneration in Drosophila. A genetic modifier screen implicated endolysosomal and axon guidance genes, including the netrin receptor, Unc-5, as key modulators of UBQLN2 toxicity. Reduced gene dosage ofUnc-5or its coreceptorDcc/frazzleddiminished neurodegenerative phenotypes, including motor dysfunction, neuromuscular junction defects, and shortened lifespan, in flies expressing UBQLN2^ALSalleles. Induced pluripotent stem cells (iPSCs) harboring UBQLN2^ALSknockin mutations exhibited lysosomal defects while inducible motor neurons (iMNs) expressing UBQLN2^ALSalleles exhibited cytosolic UBQLN2 inclusions, reduced neurite complexity, and growth cone defects that were partially reversed by silencing of UNC5B and DCC. The combined findings suggest that altered growth cone dynamics are a conserved pathomechanism in UBQLN2-associated ALS/FTD.