Abstract
Mutations in or dys-regulation of the TDP-43 gene have been associated with TDP-43 proteinopathy, a spectrum of neurodegenerative diseases including Frontotemporal Lobar Degeneration (FTLD) and Amyotrophic Lateral Sclerosis (ALS). The underlying molecular and cellular defects, however, remain unclear. Here, we report a systematic study combining analyses of patient brain samples with cellular and animal models for TDP-43 proteinopathy. Electron microscopy (EM) analyses of patient samples revealed prominent mitochondrial impairment, including abnormal cristae and a loss of cristae; these ultrastructural changes were consistently observed in both cellular and animal models of TDP-43 proteinopathy. In these models, increased TDP-43 expression induced mitochondrial dysfunction, including decreased mitochondrial membrane potential and elevated production of reactive oxygen species (ROS). TDP-43 expression suppressed mitochondrial complex I activity and reduced mitochondrial ATP synthesis. Importantly, TDP-43 activated the mitochondrial unfolded protein response (UPRmt) in both cellular and animal models. Downregulating mitochondrial protease LonP1 increased mitochondrial TDP-43 levels and exacerbated TDP-43-induced mitochondrial damage as well as neurodegeneration. Together, our results demonstrate that TDP-43 induced mitochondrial impairment is a critical aspect in TDP-43 proteinopathy. Our work has not only uncovered a previously unknown role of LonP1 in regulating mitochondrial TDP-43 levels, but also advanced our understanding of the pathogenic mechanisms for TDP-43 proteinopathy. Our study suggests that blocking or reversing mitochondrial damage may provide a potential therapeutic approach to these devastating diseases.
Original language | English (US) |
---|---|
Article number | e1007947 |
Journal | PLoS genetics |
Volume | 15 |
Issue number | 5 |
DOIs | |
State | Published - May 2019 |
Funding
JD, PW, JL and LZ are supported by grants from the National Natural Science Foundation of China (31671174; 31501133; 31671452; 31701004) and from CAS Interdisciplinary Innovation Team. JD has been supported by a grant from the China Postdoctoral Science Foundation (2016M600137). PW is supported by a grant from the China Postdoctoral Science Foundation (2018M641498). TW is supported by the Chinese Ministry of Science and Technology (2014CB849700). JYW has been supported by ALS Therapy Alliance and NIH (RO1CA175360; RO1NS107396). EB and MM are supported by NIH (P30 AG13854; P30 AG016976; DC008552; AG045571). WAM is supported by NIH (F30 NS090893). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
ASJC Scopus subject areas
- Ecology, Evolution, Behavior and Systematics
- Molecular Biology
- Genetics
- Genetics(clinical)
- Cancer Research