FUS seeds induce aggregation and spread of endogenous FUS within the brain, exacerbating neurodegeneration


Scientific Other

Poster Number: 234


Fatima Gasset, PhD


1. Ludwig Instituite for Cancer Research

RNA binding proteins have emerged as central players in the mechanisms underlying many of the most prominent neurodegenerative diseases. In particular, mutations in Fused in sarcoma (FUS) cause Amyotrophic lateral sclerosis (ALS) and Frontotemporal dementia (FTD) and are major protein components of pathological inclusions of FUS-mutant-mediated ALS or FTD. Aggregates of FUS have been found in familial ALS and FTD, rare cases of sporadic ALS, and almost universally in sporadic FTD. However, it is not known if there is a correlation between severity of disease and the nature of neuropathological inclusions, nor is it established whether the neuropathology of clinical ALS reflects the heterogeneity of the disorder, a well-recognized feature of many neurodegenerative conditions. One time focal injection of fibrilized/aggregated human FUS into humanized mice (in which ALS-linked mutant or wildtype FUS mice replaces endogenous FUS) induced cytoplasmic mislocalization and aggregation of FUS (mutant or wild type) initially in areas in contact with the injected FUS seeds, later spreading to distal regions in a prion-like fashion. FUS aggregates are ubiquitin positive, resembling the amyloid-like, insoluble ones found in patients. Fibril-injection exacerbated age-dependent cognitive impairments associated with mutant FUS expression and initiated motor deficits. Thus, focal FUS aggregation (by injection or produced stoichastically by misfolding of wild type FUS) can spread from cell-to-cell in a prion-like fashion exacerbating disease initiation and/or progression, providing a model for sporadic human FUS proteinopathy