Project Grant R21NS147268

The National Institute of Neurological Disorders and Stroke awarded the University of Wisconsin–Madison $427,625 on August 1, 2026, under the Extramural Research Programs in the Neurosciences and Neurological Disorders program (CFDA 93.853).

The recipient is conducting basic research to understand how axon guidance genes contribute to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two neurodegenerative disorders that share a clinical disease spectrum. The research focuses on X-linked mutations in the ubiquitin chaperone UBQLN2, which cause diverse neurologic phenotypes ranging from pure ALS with or without FTD to primary lateral sclerosis and spastic paraplegia. The research employs a "fly to human" approach combining genetic modifier screens in Drosophila with testing in inducible pluripotent stem cell–derived motor neurons (IMNs) containing ALS-associated UBQLN2 mutations. Unbiased genetic screens identified the UNC-5 and frazzled (FRA) axon guidance genes as determinants of UBQLN2 toxicity; suppression of human UNC5B, UNC5C, and DCC orthologs suppressed toxicity phenotypes in human IMNs carrying UBQLN2 mutations.

The award supports work at the University of Wisconsin–Madison campus in Madison, Wisconsin. The period of performance runs from August 1, 2026, through July 31, 2028.