Document Type
Article
Publication Date
6-11-2024
Abstract
RNA binding proteins have emerged as central players in the mechanisms of many neurodegenerative diseases. In particular, a proteinopathy of fused in sarcoma (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.
Recommended Citation
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; Shorter, James; and Da Cruz, Sandrine, "Frontotemporal Dementia-Like Disease Progression Elicited by Seeded Aggregation and Spread of FUS" (2024). Department of Biochemistry and Molecular Biology Faculty Papers. Paper 258.
https://jdc.jefferson.edu/bmpfp/258
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
PubMed ID
38862967
Language
English
Included in
Biochemistry Commons, Medical Sciences Commons, Molecular Biology Commons, Nervous System Diseases Commons
Comments
This article is the author's final published version in Molecular Neurodegeneration, Volume 19, Issue 1, 2024, Article number 46.
The published version is available at https://doi.org/10.1186/s13024-024-00737-5.
Copyright © The Author(s) 2024