Journal
MOLECULAR PSYCHIATRY
Volume 26, Issue 7, Pages 2721-2739Publisher
SPRINGERNATURE
DOI: 10.1038/s41380-021-01050-z
Keywords
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Funding
- Biotechnology and Biological Sciences Research Council [BB/M010384/1, BB/N007042/1]
- BBSRC LiDO Studentship Scheme
- Umberto Veronesi Foundation Young Investigator Award Programme
- Marie Curie Brain [CIG 304165 _TSPO]
- LAM-Bighi Grant Initiative
- Rotary Foundation
- European Research Council [COG -819600_FIRM]
- Parkinson's UK [F1301]
- National Institute for Health Research and Hospitals Biomedical Research Centre UCLH
- BBSRC [BB/N007042/1, BB/N009088/1] Funding Source: UKRI
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The 18 kDa Translocator Protein (TSPO) plays a critical role in Parkinson's Disease by enhancing cellular redox-stress, susceptibility to dopamine-induced cell death, and repression of ubiquitin-dependent mitophagy. TSPO amplifies ERK1/2 signalling, represses TFEB, and is required to alter the autophagy-lysosomal pathway during neurotoxicity.
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.
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