{Reference Type}: Journal Article
{Title}: Frontotemporal dementia-like disease progression elicited by seeded aggregation and spread of FUS.
{Author}: Vazquez-Sanchez S;Tilkin B;Gasset-Rosa F;Zhang S;Piol D;McAlonis-Downes M;Artates J;Govea-Perez N;Verresen Y;Guo L;Cleveland DW;Shorter J;Da Cruz S;
{Journal}: Mol Neurodegener
{Volume}: 19
{Issue}: 1
{Year}: 2024 Jun 11
{Factor}: 18.879
{DOI}: 10.1186/s13024-024-00737-5
{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.