A new study from scientists at VIB-KU Leuven Center for Brain & Disease and elsewhere reveals the role of an RNA binding protein called Fused in Sarcoma (FUS) in the development of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Details are provided in a paper published in Molecular Neurodegeneration titled, “Frontotemporal dementia-like disease progression elicited by seeded aggregation and spread of FUS.”
The results from the study support a long suspected belief about the role of the FUS protein in neurodegenerative diseases. Normally FUS protein resides in the cell’s nucleus but in some patients, it clumps into aggregates in the cytoplasm. Now, scientists led by Sandrine Da Cruz, PhD, a professor and head of the laboratory of neurophysiology in neurodegenerative disorders at VIB-KU Leuven have demonstrated how FUS aggregates spread and behave in neurodegenerative diseases.
According to the paper, the scientists injected disease-associated human FUS aggregates into adult mice engineered to express human FUS protein. The aggregates acted like seeds causing the existing human FUS protein in the mice to aggregate and spread to other regions of the brain. The aggregated proteins exacerbated age-dependent cognitive decline and behavioral deficit in the mice. It mirrored the way protein aggregates form and spread in FTLD and ALS patients.
“This finding suggests a prion-like mechanism, which is a process where proteins misfold and cause other proteins to misfold in a similar way, leading to the spread of disease within a body,” said Sonia Vazquez-Sanchez, PhD, who is the co-first author of the study. In fact, their results “contribute to the mounting evidence that prion-like transmission of misfolded proteins represents a common process in the pathogenesis of several neurodegenerative diseases” including Parkinson’s and Alzheimer’s disease, the team wrote.
The process is also species specific, according to the findings. The scientists did not observe the protein aggregation process when they injected aggregates into mice that expressed wild-type FUS.
Vazquez-Sanchez further noted that “identifying the exact components of these aggregates and the brain regions most affected by their spread will be crucial for developing future therapeutic interventions.”
New therapies would be a boon for patients with FTLD, which accounts for approximately 10–20% of dementia cases and is characterized by changes in personality, behavior, and language due to damaged frontal and temporal lobes. For its part, ALS is characterized by a selective loss of motor neurons, resulting in progressive muscle weakness and paralysis, as well as swallowing and speech difficulties. Therapeutic strategies that target the spread of FUS protein aggregates could ultimately help halt or slow the progression of both conditions.