Summary: A new study reveals how the FUS protein aggregates and spreads in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS).
Research shows that misfolded FUS proteins act like prions, spreading disease in the brain and exacerbating neurodegeneration. This discovery opens new avenues for therapeutic strategies targeting the propagation of protein aggregates.
Highlights:
- FUS protein aggregates spread like prions, contributing to neurodegeneration in FTD and ALS.
- FUS aggregates injected into mice caused cognitive decline and behavioral deficits.
- Understanding the mechanisms of FUS aggregation may lead to new therapies for neurodegenerative diseases.
Source: VIB
Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two devastating neurodegenerative diseases. Scientists have long suspected that a protein called FUS might play a role, but the exact mechanism remains a mystery.
A new study from the laboratory of Professor Sandrine Da Cruz published in Molecular neurodegeneration reveals the behavior of the FUS protein in these diseases, which is crucial for possible therapeutic interventions.
Frontotemporal dementia (FTD) is a form of early-onset dementia, accounting for approximately 10-20% of dementia cases. Unlike Alzheimer’s disease, which primarily affects memory, FTD is characterized by changes in personality, behavior, and language due to degeneration of the brain’s frontal and temporal lobes.
Amyotrophic lateral sclerosis (ALS), the most common degenerative motor neuron disease in adults, is characterized by selective loss of motor neurons, leading to progressive muscle weakness and paralysis, as well as difficulty swallowing and speaking.
Patients typically succumb to the disease within 2 to 5 years of diagnosis. Every year, approximately 100,000 people die from ALS.
In these two diseases, a protein called “Fused in sarcoma” (FUS) poses a problem. Normally, FUS resides primarily in the nucleus of the cell, but in some patients it clumps (aggregates) in the cytoplasm.
A new study, led by Professor Sandrine Da Cruz from the Center for Brain and Disease Research VIB-KU Leuven, reveals how these FUS aggregates spread and behave, contributing to neurodegeneration.
Spread of disease
The researchers injected disease-associated human FUS aggregates into mice engineered to express human FUS protein. Remarkably, the aggregates acted like seeds, causing the endogenous human FUS protein in the mouse to aggregate and spread to other regions of the brain.
“This finding suggests a prion-like mechanism, which is a process in which proteins misfold and cause other proteins to misfold in the same way, leading to the spread of diseases in the body,” explains Dr. Sonia Vazquez-Sanchez, co-first author of the study.
“In this case, misfolded FUS aggregates ‘corrupted’ healthy FUS proteins, resulting in a domino effect of harmful FUS aggregation throughout the brain.”
FUS protein aggregation exacerbated age-related cognitive decline and behavioral deficits in mice. This process mirrors what is observed in human FTD and ALS, where protein aggregates spread and contribute to neurodegeneration.
Another important discovery was the species barrier to FUS aggregation. When human FUS fibrils were injected into mice, which express only mouse FUS, no aggregation occurred. This indicates that specific interactions between human FUS proteins may be required for aggregation and spreading.
Implications and future directions
This research supports the broader hypothesis that many neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease, may involve prion-like mechanisms in which misfolded proteins spread by inducing similar misfolding in normal proteins. Understanding these mechanisms opens new avenues for therapeutic strategies aimed at stopping or slowing disease progression by targeting the spread of protein aggregates.
The research team is currently studying the specifics of neurodegeneration induced by FUS aggregates.
“Identifying the exact components of these aggregates and the brain regions most affected by their propagation will be crucial for developing future therapeutic interventions,” concludes Professor Sandrine Da Cruz.
Funding and collaborations
Advances in research are only possible through collaborations at the national and international levels. This research was conducted in close collaboration between the laboratories of Professor Sandrine Da Cruz, Professor James Shorter (UPenn), Professor Don Cleveland (UCSD), and Professor Lin Guo (Thomas Jefferson).
The research (team) was supported by the Research Foundation Flanders (FWO), the Muscular Dystrophy Association, the Fondation Recherche Alzheimer – Stichting Alzheimer Onderzoek (STOPALZHEIMER.BE), Target ALS, ALSA and the Robert Packard Center for ALS Research at Johns Hopkins. .
About this research news in neurology and genetics
Author: India Jane Wise
Source: VIB
Contact: India Jane Wise – VIB
Picture: Image is credited to Neuroscience News
Original research: Free access.
“Progression of frontotemporal dementia-like disease caused by seeded aggregation and spread of FUS” by Sandrine Da Cruz et al. Molecular neurodegeneration
Abstract
Progression of frontotemporal dementia-like disease caused by seeded aggregation and spread of FUS
RNA-binding proteins have become central players in the mechanisms of many neurodegenerative diseases. In particular, fused sarcoma proteinopathy (FUS) is present in some cases of familial amyotrophic lateral sclerosis (ALS) and approximately 10% of sporadic frontotemporal lobar degeneration (FTLD).
We establish here that focal injection of sonicated human FUS fibrils into mouse brains in which ALS-related mutant or wild-type human FUS replaces endogenous mouse FUS is sufficient to induce focal cytoplasmic mislocalization and l aggregation of mutant and wild-type FUS which, over time. spreads to distal regions of the brain.
FUS aggregation induced by human FUS fibrils in the brain of humanized FUS mice is accelerated by an ALS-causing mutant FUS compared to wild-type human FUS.
Injection of sonicated human FUS fibrils does not induce FUS aggregation or subsequent propagation after injection into naive mouse brains containing only mouse FUS, indicating a species barrier to FUS aggregation. Human FUS and its prion-like propagation.
Fibril-induced human FUS aggregates recapitulate the pathological features of FTLD, including increased insolubility of FUS and TAF15 in detergents and cytoplasmic deposits of amyloid-like FUS that accumulate ubiquitin and p62, but not the TDP-43.
Finally, injection of sonicated FUS fibrils has been shown to exacerbate age-related cognitive and behavioral deficits due to expression of mutant human FUS. Thus, seeded focal aggregation of FUS and its subsequent spread by prion-like propagation causes FUS proteinopathy and FTLD-like disease progression.