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| 001 | 139474 | ||
| 005 | 20240722112243.0 | ||
| 024 | 7 | _ | |a 10.1093/brain/awx202 |2 doi |
| 024 | 7 | _ | |a pmid:29050400 |2 pmid |
| 024 | 7 | _ | |a 0006-8950 |2 ISSN |
| 024 | 7 | _ | |a 1460-2156 |2 ISSN |
| 024 | 7 | _ | |a altmetric:24506165 |2 altmetric |
| 037 | _ | _ | |a DZNE-2020-05796 |
| 041 | _ | _ | |a English |
| 082 | _ | _ | |a 610 |
| 100 | 1 | _ | |a Fitzgerald, Julia |0 P:(DE-2719)2812175 |b 0 |e First author |
| 245 | _ | _ | |a Metformin reverses TRAP1 mutation-associated alterations in mitochondrial function in Parkinson's disease. |
| 260 | _ | _ | |a Oxford |c 2017 |b Oxford Univ. Press |
| 264 | _ | 1 | |3 online |2 Crossref |b Oxford University Press (OUP) |c 2017-08-24 |
| 264 | _ | 1 | |3 print |2 Crossref |b Oxford University Press (OUP) |c 2017-09-01 |
| 336 | 7 | _ | |a article |2 DRIVER |
| 336 | 7 | _ | |a Output Types/Journal article |2 DataCite |
| 336 | 7 | _ | |a Journal Article |b journal |m journal |0 PUB:(DE-HGF)16 |s 1721640140_12031 |2 PUB:(DE-HGF) |
| 336 | 7 | _ | |a ARTICLE |2 BibTeX |
| 336 | 7 | _ | |a JOURNAL_ARTICLE |2 ORCID |
| 336 | 7 | _ | |a Journal Article |0 0 |2 EndNote |
| 520 | _ | _ | |a The mitochondrial proteins TRAP1 and HTRA2 have previously been shown to be phosphorylated in the presence of the Parkinson's disease kinase PINK1 but the downstream signalling is unknown. HTRA2 and PINK1 loss of function causes parkinsonism in humans and animals. Here, we identified TRAP1 as an interactor of HTRA2 using an unbiased mass spectrometry approach. In our human cell models, TRAP1 overexpression is protective, rescuing HTRA2 and PINK1-associated mitochondrial dysfunction and suggesting that TRAP1 acts downstream of HTRA2 and PINK1. HTRA2 regulates TRAP1 protein levels, but TRAP1 is not a direct target of HTRA2 protease activity. Following genetic screening of Parkinson's disease patients and healthy controls, we also report the first TRAP1 mutation leading to complete loss of functional protein in a patient with late onset Parkinson's disease. Analysis of fibroblasts derived from the patient reveal that oxygen consumption, ATP output and reactive oxygen species are increased compared to healthy individuals. This is coupled with an increased pool of free NADH, increased mitochondrial biogenesis, triggering of the mitochondrial unfolded protein response, loss of mitochondrial membrane potential and sensitivity to mitochondrial removal and apoptosis. These data highlight the role of TRAP1 in the regulation of energy metabolism and mitochondrial quality control. Interestingly, the diabetes drug metformin reverses mutation-associated alterations on energy metabolism, mitochondrial biogenesis and restores mitochondrial membrane potential. In summary, our data show that TRAP1 acts downstream of PINK1 and HTRA2 for mitochondrial fine tuning, whereas TRAP1 loss of function leads to reduced control of energy metabolism, ultimately impacting mitochondrial membrane potential. These findings offer new insight into mitochondrial pathologies in Parkinson's disease and provide new prospects for targeted therapies. |
| 536 | _ | _ | |a 345 - Population Studies and Genetics (POF3-345) |0 G:(DE-HGF)POF3-345 |c POF3-345 |f POF III |x 0 |
| 588 | _ | _ | |a Dataset connected to CrossRef, PubMed, |
| 650 | _ | 7 | |a HSP90 Heat-Shock Proteins |2 NLM Chemicals |
| 650 | _ | 7 | |a Mitochondrial Proteins |2 NLM Chemicals |
| 650 | _ | 7 | |a Reactive Oxygen Species |2 NLM Chemicals |
| 650 | _ | 7 | |a TRAP1 protein, human |2 NLM Chemicals |
| 650 | _ | 7 | |a NAD |0 0U46U6E8UK |2 NLM Chemicals |
| 650 | _ | 7 | |a Adenosine Triphosphate |0 8L70Q75FXE |2 NLM Chemicals |
| 650 | _ | 7 | |a Metformin |0 9100L32L2N |2 NLM Chemicals |
| 650 | _ | 7 | |a Protein Kinases |0 EC 2.7.- |2 NLM Chemicals |
| 650 | _ | 7 | |a PTEN-induced putative kinase |0 EC 2.7.11.1 |2 NLM Chemicals |
| 650 | _ | 7 | |a Serine Endopeptidases |0 EC 3.4.21.- |2 NLM Chemicals |
| 650 | _ | 7 | |a HTRA2 protein, human |0 EC 3.4.21.108 |2 NLM Chemicals |
| 650 | _ | 7 | |a High-Temperature Requirement A Serine Peptidase 2 |0 EC 3.4.21.108 |2 NLM Chemicals |
| 650 | _ | 2 | |a Adenosine Triphosphate: metabolism |2 MeSH |
| 650 | _ | 2 | |a Apoptosis: drug effects |2 MeSH |
| 650 | _ | 2 | |a Case-Control Studies |2 MeSH |
| 650 | _ | 2 | |a Cells, Cultured |2 MeSH |
| 650 | _ | 2 | |a Fibroblasts: metabolism |2 MeSH |
| 650 | _ | 2 | |a HSP90 Heat-Shock Proteins: biosynthesis |2 MeSH |
| 650 | _ | 2 | |a HSP90 Heat-Shock Proteins: genetics |2 MeSH |
| 650 | _ | 2 | |a High-Temperature Requirement A Serine Peptidase 2 |2 MeSH |
| 650 | _ | 2 | |a Humans |2 MeSH |
| 650 | _ | 2 | |a Membrane Potential, Mitochondrial: physiology |2 MeSH |
| 650 | _ | 2 | |a Metformin: therapeutic use |2 MeSH |
| 650 | _ | 2 | |a Mitochondria: drug effects |2 MeSH |
| 650 | _ | 2 | |a Mitochondria: genetics |2 MeSH |
| 650 | _ | 2 | |a Mitochondria: metabolism |2 MeSH |
| 650 | _ | 2 | |a Mitochondrial Proteins: metabolism |2 MeSH |
| 650 | _ | 2 | |a Mutation |2 MeSH |
| 650 | _ | 2 | |a NAD: metabolism |2 MeSH |
| 650 | _ | 2 | |a Organelle Biogenesis |2 MeSH |
| 650 | _ | 2 | |a Oxygen Consumption |2 MeSH |
| 650 | _ | 2 | |a Parkinson Disease: drug therapy |2 MeSH |
| 650 | _ | 2 | |a Parkinson Disease: genetics |2 MeSH |
| 650 | _ | 2 | |a Parkinson Disease: metabolism |2 MeSH |
| 650 | _ | 2 | |a Protein Kinases: metabolism |2 MeSH |
| 650 | _ | 2 | |a Reactive Oxygen Species: metabolism |2 MeSH |
| 650 | _ | 2 | |a Serine Endopeptidases: metabolism |2 MeSH |
| 700 | 1 | _ | |a Zimprich, Alexander |0 P:(DE-HGF)0 |b 1 |
| 700 | 1 | _ | |a Carvajal Berrio, Daniel A |0 P:(DE-HGF)0 |b 2 |
| 700 | 1 | _ | |a Schindler, Kevin M |0 P:(DE-2719)9000285 |b 3 |
| 700 | 1 | _ | |a Maurer, Brigitte |0 P:(DE-2719)9000205 |b 4 |
| 700 | 1 | _ | |a Schulte, Claudia |0 P:(DE-2719)9000366 |b 5 |
| 700 | 1 | _ | |a Bus, Christine |0 P:(DE-2719)2811284 |b 6 |
| 700 | 1 | _ | |a Hauser, Ann-Kathrin |0 P:(DE-2719)2351249 |b 7 |
| 700 | 1 | _ | |a Kübler, Manuela |0 P:(DE-2719)9000170 |b 8 |
| 700 | 1 | _ | |a Lewin, Rahel |0 P:(DE-2719)9000185 |b 9 |
| 700 | 1 | _ | |a Bobbili, Dheeraj Reddy |0 P:(DE-HGF)0 |b 10 |
| 700 | 1 | _ | |a Schwarz, Lisa M |0 P:(DE-2719)9000438 |b 11 |
| 700 | 1 | _ | |a Vartholomaiou, Evangelia |0 P:(DE-HGF)0 |b 12 |
| 700 | 1 | _ | |a Brockmann, Kathrin |0 P:(DE-2719)2811916 |b 13 |
| 700 | 1 | _ | |a Wüst, Richard |0 P:(DE-2719)9000353 |b 14 |
| 700 | 1 | _ | |a Madlung, Johannes |0 P:(DE-HGF)0 |b 15 |
| 700 | 1 | _ | |a Nordheim, Alfred |0 P:(DE-HGF)0 |b 16 |
| 700 | 1 | _ | |a Riess, Olaf |0 P:(DE-HGF)0 |b 17 |
| 700 | 1 | _ | |a Martins, L Miguel |0 P:(DE-HGF)0 |b 18 |
| 700 | 1 | _ | |a Glaab, Enrico |0 P:(DE-HGF)0 |b 19 |
| 700 | 1 | _ | |a May, Patrick |0 P:(DE-HGF)0 |b 20 |
| 700 | 1 | _ | |a Schenke-Layland, Katja |0 P:(DE-HGF)0 |b 21 |
| 700 | 1 | _ | |a Picard, Didier |0 P:(DE-HGF)0 |b 22 |
| 700 | 1 | _ | |a Sharma, Manu |0 P:(DE-HGF)0 |b 23 |
| 700 | 1 | _ | |a Gasser, Thomas |0 P:(DE-2719)2320009 |b 24 |
| 700 | 1 | _ | |a Krüger, Rejko |0 P:(DE-2719)2811170 |b 25 |e Last author |
| 773 | 1 | 8 | |a 10.1093/brain/awx202 |b : Oxford University Press (OUP), 2017-08-24 |n 9 |p 2444-2459 |3 journal-article |2 Crossref |t Brain |v 140 |y 2017 |x 0006-8950 |
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