Reference - Detail
| RRC ID | 57126 |
|---|---|
| Author | Wang P, Deng J, Dong J, Liu J, Bigio EH, Mesulam M, Wang T, Sun L, Wang L, Lee AY, McGee WA, Chen X, Fushimi K, Zhu L, Wu JY. |
| Title | TDP-43 induces mitochondrial damage and activates the mitochondrial unfolded protein response. |
| Journal | PLoS Genet |
| 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. Down-regulating 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. |
| Volume | 15(5) |
| Pages | e1007947 |
| Published | 2019-5-1 |
| DOI | 10.1371/journal.pgen.1007947 |
| PII | PGENETICS-D-18-00456 |
| PMID | 31100073 |
| PMC | PMC6524796 |
| MeSH | ATP-Dependent Proteases / genetics* ATP-Dependent Proteases / metabolism Adenosine Triphosphate / biosynthesis Amyotrophic Lateral Sclerosis / genetics* Amyotrophic Lateral Sclerosis / metabolism Amyotrophic Lateral Sclerosis / pathology Animals Brain / metabolism Brain / pathology DNA-Binding Proteins / genetics* DNA-Binding Proteins / metabolism Disease Models, Animal Drosophila melanogaster Electron Transport Complex I / genetics Electron Transport Complex I / metabolism Frontotemporal Lobar Degeneration / genetics* Frontotemporal Lobar Degeneration / metabolism Frontotemporal Lobar Degeneration / pathology Gene Expression Regulation HEK293 Cells Humans Membrane Potential, Mitochondrial / genetics Mitochondria / metabolism Mitochondria / pathology Mitochondrial Proteins / genetics* Mitochondrial Proteins / metabolism Mutation Reactive Oxygen Species / metabolism Signal Transduction TDP-43 Proteinopathies / genetics* TDP-43 Proteinopathies / metabolism TDP-43 Proteinopathies / pathology Unfolded Protein Response* |
| IF | 5.224 |
| Times Cited | 16 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | X(Twitter) |
| Total number of mentions | 23 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Drosophila | DGRC#108330 |