The translocator protein (TSPO) is prodromal to mitophagy loss in neurotoxicity.

Autor: Frison M; Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, Royal College Street, London, United Kingdom.; MRC Mitochondrial Biology Unit, Cambridge Biomedical Campus, Cambridge, United Kingdom., Faccenda D; Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, Royal College Street, London, United Kingdom., Abeti R; Ataxia Centre, Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Queen Square London, United Kingdom., Rigon M; Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, Royal College Street, London, United Kingdom.; Department of Biology, University of Rome TorVergata, Via della Ricerca Scientifica, Rome, Italy., Strobbe D; Department of Biology, University of Rome TorVergata, Via della Ricerca Scientifica, Rome, Italy., England-Rendon BS; Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, Royal College Street, London, United Kingdom., Cash D; Department of Neuroimaging, Institute of Psychiatry, King's College London, Camberwell, United Kingdom., Barnes K; Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, United Kingdom., Sadeghian M; Department of Neuroinflammation, UCL Queen Square Institute of Neurology, London, United Kingdom., Sajic M; Department of Neuroinflammation, UCL Queen Square Institute of Neurology, London, United Kingdom., Wells LA; Imanova Limited, Centre for Imaging Sciences, Imperial College London, Hammersmith Hospital, London, United Kingdom., Xia D; Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, Royal College Street, London, United Kingdom., Giunti P; Ataxia Centre, Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Queen Square London, United Kingdom., Smith K; Department of Neuroinflammation, UCL Queen Square Institute of Neurology, London, United Kingdom., Mortiboys H; Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, United Kingdom., Turkheimer FE; Department of Neuroimaging, Institute of Psychiatry, King's College London, Camberwell, United Kingdom., Campanella M; Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, Royal College Street, London, United Kingdom. mcampanella@rvc.ac.uk.; Department of Biology, University of Rome TorVergata, Via della Ricerca Scientifica, Rome, Italy. mcampanella@rvc.ac.uk.; University College London Consortium for Mitochondrial Research, London, United Kingdom. mcampanella@rvc.ac.uk.
Jazyk: angličtina
Zdroj: Molecular psychiatry [Mol Psychiatry] 2021 Jul; Vol. 26 (7), pp. 2721-2739. Date of Electronic Publication: 2021 Mar 04.
DOI: 10.1038/s41380-021-01050-z
Abstrakt: Dysfunctional mitochondria characterise Parkinson's Disease (PD). Uncovering etiological molecules, which harm the homeostasis of mitochondria in response to pathological cues, is therefore pivotal to inform early diagnosis and therapy in the condition, especially in its idiopathic forms. This study proposes the 18 kDa Translocator Protein (TSPO) to be one of those. Both in vitro and in vivo data show that neurotoxins, which phenotypically mimic PD, increase TSPO to enhance cellular redox-stress, susceptibility to dopamine-induced cell death, and repression of ubiquitin-dependent mitophagy. TSPO amplifies the extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) signalling, forming positive feedback, which represses the transcription factor EB (TFEB) and the controlled production of lysosomes. Finally, genetic variances in the transcriptome confirm that TSPO is required to alter the autophagy-lysosomal pathway during neurotoxicity.
(© 2021. The Author(s), under exclusive licence to Springer Nature Limited part of Springer Nature.)
Databáze: MEDLINE
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