Northwestern Medicine scientists have demonstrated that damage to mitochondria plays a critical early role in a group of neurogenerative diseases, including forms of amyotrophic lateral sclerosis (ALS) and dementia.
“Our study suggests that blocking or reversing mitochondrial damage may provide a therapeutic approach to these devastating diseases,” said Jane Wu, MD, PhD, the Dr. Charles L. Mix Research Professor of Neurology and Psychiatry, and co-corresponding author of the study published in Proceedings of the National Academy of Sciences.
The current findings point to a critical role for mitochondrial damage in FUS proteinopathy, a group of neurogenerative diseases characterized by accumulations of the protein FUS, which include some inherited forms of ALS and frontotemporal dementia.
Previously, research led by Wu and others had suggested that mitochondrial dysfunction may be an important aspect of FUS proteinopathy. However, the molecular mechanisms by which FUS damages mitochondria had remained unclear.
In the current study, investigators demonstrated in cellular and animal models that mitochondrial damage is the earliest detectable defect of FUS proteinopathy — with similar damage also detected in patient samples.
Furthermore, the scientists provided new insights into the particular mechanisms behind the disease: FUS, a nuclear protein, can move into mitochondria, where it disrupts normal function of ATP5B — the catalytic subunit of the key mitochondrial enzyme ATP — and activates the mitochondrial unfolded protein response (UPRmt).
“These findings uncover a previously unknown mechanism of modulating mitochondrial ATP synthesis and advance our understanding of mechanisms underlying FUS proteinopathy,” said Wu, a professor of Neurology in the Division of Neuromuscular Disease.
The study also has potential therapeutic implications: In their experiments, the team demonstrated that down-regulating expression of ATP5B or UPRmt genes improves neurodegenerative phenotypes in a fly model.
Mitochondrial impairment could also potentially serve as a diagnostic biomarker for FUS-associated neurodegenerative diseases, Wu notes.
In future research, the Wu laboratory aims to investigate mechanisms by which FUS accumulates in mitochondria and induces the mitochondrial unfolded protein response. They also aim to identify modifier genes for FUS proteinopathy and new approaches to blocking or reversing FUS-induced neural damage.
Other Northwestern co-authors of the paper include Kazuo Fushimi, PhD, research assistant professor of Neurology in the Division of Neuromuscular Disease; Haipeng Cheng, PhD, a postdoctoral fellow; and Xiaoping Chen, a research associate in the Wu lab.
Wu is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
The study, a collaboration between Northwestern and the Chinese Academy of Sciences in Beijing, was supported by National Institutes of Health grants to Wu, and grants from the National Natural Science Foundation of China and the China Postdoctoral Science Foundation to Li Zhu and Jianwen Deng, respectively.
