Axon guidance genes modulate neurotoxicity of ALS-associated UBQLN2.

Abstract

Mutations in the ubiquitin (Ub) chaperone <i>Ubiquilin 2 (UBQLN2</i>) 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 <i>Drosophila</i>. 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 of <i>Unc-5</i> or its coreceptor <i>Dcc/frazzled</i> diminished neurodegenerative phenotypes, including motor dysfunction, neuromuscular junction defects, and shortened lifespan, in flies expressing UBQLN2^ALS alleles. Induced pluripotent stem cells (iPSCs) harboring UBQLN2^ALS knockin mutations exhibited lysosomal defects while inducible motor neurons (iMNs) expressing UBQLN2^ALS alleles exhibited cytosolic UBQLN2 inclusions, reduced neurite complexity, and growth cone defects that were partially reversed by silencing of <i>UNC5B</i> and <i>DCC</i>. The combined findings suggest that altered growth cone dynamics are a conserved pathomechanism in UBQLN2-associated ALS/FTD.