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 (UBQLN2ALS) 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 UBQLN2ALSalleles. Induced pluripotent stem cells (iPSCs) harboring UBQLN2ALSknockin mutations exhibited lysosomal defects while inducible motor neurons (iMNs) expressing UBQLN2ALSalleles 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.

Functional consequences of familial ALS‐associated SOD1L84F in neuronal and muscle cells

“…Reduced levels of stathmin‐2, a microtubule regulator essential for neurite outgrowth and axonal regeneration, have been reported in motor neurons derived from fibroblasts of TDP‐43 patientswith ALS and spinal cord of patients with ALS 42,43 . In addition, mutant UBQLN2 implicated in ALS has recently been shown to cause neurite defects in drosophila and reprogrammed motor neurons 44 . Alterations in these pathways cause synaptic defects which may lead to distal axonopathy.…”

“…42,43 In addition, mutant UBQLN2 implicated in ALS has recently been shown to cause neurite defects in drosophila and reprogrammed motor neurons. 44 Alterations in these pathways cause synaptic defects which may lead to distal axonopathy. Despite the robust nature of muscle cells, transcriptome analysis showed deregulation of BDNF, MAPK, and NTRK1 signaling pathways.…”