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Brain. 2017 Sep 1;140(9):2444-2459. doi: 10.1093/brain/awx202.

Metformin reverses TRAP1 mutation-associated alterations in mitochondrial function in Parkinson's disease.

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Department of Neurodegenerative Diseases, Center of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen and German Centre for Neurodegenerative Diseases, Tübingen, Germany.
Medical University Vienna, Department of Neurology, Vienna, Austria.
Department of Women's Health, Research Institute for Women's Health, University of Tübingen, Tübingen, Germany.
University of Tübingen, Interfaculty Institute of Biochemistry, Tübingen, Germany.
Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg.
Graduate Training Centre of Neuroscience, International Max Planck Research School, Tübingen, Germany.
University of Geneva, Department of Cell Biology, Geneva, Switzerland.
Department of Psychiatry and Psychotherapie, University Hospital Tübingen, Germany.
University of Tübingen, Interfaculty Institute for Cell Biology, Proteome Center Tübingen, Tübingen, Germany.
University of Tübingen, Interfaculty Institute of Cell Biology, Unit of Molecular Biology, Tübingen, Germany.
University of Tübingen, Institute of Medical Genetics and Applied Genomics, Tübingen, Germany.
MRC Toxicology Unit, University of Leicester, Leicester, UK.
Department of Cell and Tissue Engineering, Fraunhofer Institute for Interfacial Engineering and Biotechnology IGB Stuttgart, Germany.
Department of Medicine/ Cardiology, CVRL, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Germany.
Parkinson Research Clinic, Centre Hospitalier de Luxembourg (CHL), Luxembourg.


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.


Parkinson’s disease; experimental models; metabolic disease; mitochondrial diseases; neuroprotection

[Indexed for MEDLINE]

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