Frontotemporal dementia-like disease progression elicited by seeded aggregation and spread of FUS

• Published in: Molecular neurodegeneration Vol. 19; no. 1; pp. 46 - 15
• Main Authors: Vazquez-Sanchez, Sonia, Tilkin, Britt, Gasset-Rosa, Fatima, Zhang, Sitao, Piol, Diana, McAlonis-Downes, Melissa, Artates, Jonathan, Govea-Perez, Noe, Verresen, Yana, Guo, Lin, Cleveland, Don W., Shorter, James, Da Cruz, Sandrine
• Format: Journal Article
• Language: English
• Published: London BioMed Central 11.06.2024; BioMed Central Ltd; BMC
• Subjects: Aggregation; Amyotrophic lateral sclerosis; Amyotrophic lateral sclerosis (ALS); Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Animals; Binding proteins; Biomedical and Life Sciences; Biomedicine; Brain; Brain - metabolism; Brain - pathology; Development and progression; Disease Models, Animal; Disease Progression; Ethylenediaminetetraacetic acid; Frontotemporal Dementia - genetics; Frontotemporal Dementia - metabolism; Frontotemporal Dementia - pathology; Frontotemporal lobar degeneration (FTLD); FUS-proteinopathy; Genetic aspects; Humans; Mice; Mice, Transgenic; Molecular Medicine; Nervous system diseases; Neurology; Neurosciences; Protein Aggregation, Pathological - metabolism; Protein binding; Research Article; RNA-Binding Protein FUS - genetics; RNA-Binding Protein FUS - metabolism; Sarcoma; Spreading; Aggregation; FUS-proteinopathy; Frontotemporal lobar degeneration (FTLD); Amyotrophic lateral sclerosis (ALS); Spreading
• ISSN: 1750-1326; 1750-1326
• DOI: 10.1186/s13024-024-00737-5

RNA binding proteins have emerged as central players in the mechanisms of many neurodegenerative diseases. In particular, a proteinopathy of fu sed in s arcoma (FUS) is present in some instances of familial Amyotrophic lateral sclerosis (ALS) and about 10% of sporadic Frontotemporal lobar degeneration (FTLD). Here we establish that focal injection of sonicated human FUS fibrils into brains of mice in which ALS-linked mutant or wild-type human FUS replaces endogenous mouse FUS is sufficient to induce focal cytoplasmic mislocalization and aggregation of mutant and wild-type FUS which with time spreads to distal regions of the brain. Human FUS fibril-induced FUS aggregation in the mouse brain of humanized FUS mice is accelerated by an ALS-causing FUS mutant relative to wild-type human FUS. Injection of sonicated human FUS fibrils does not induce FUS aggregation and subsequent spreading after injection into naïve mouse brains containing only mouse FUS, indicating a species barrier to human FUS aggregation and its prion-like spread. Fibril-induced human FUS aggregates recapitulate pathological features of FTLD including increased detergent insolubility of FUS and TAF15 and amyloid-like, cytoplasmic deposits of FUS that accumulate ubiquitin and p62, but not TDP-43. Finally, injection of sonicated FUS fibrils is shown to exacerbate age-dependent cognitive and behavioral deficits from mutant human FUS expression. Thus, focal seeded aggregation of FUS and further propagation through prion-like spread elicits FUS-proteinopathy and FTLD-like disease progression.