The translocator protein (TSPO) is prodromal to mitophagy loss in neurotoxicity.
Michele FrisonDanilo FaccendaRosella AbetiManuel RigonDaniela StrobbeBritannie S England-RendonDiana CashKaty BarnesMona SadeghianMarija SajicLisa A WellsDong XiaPaola GiuntiKenneth SmithHeather MortiboysFederico Edoardo TurkheimerMichelangelo CampanellaPublished in: Molecular psychiatry (2021)
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.
Keyphrases
- positron emission tomography
- pet imaging
- cell death
- transcription factor
- pet ct
- signaling pathway
- protein kinase
- cell cycle arrest
- genome wide
- gene expression
- cell proliferation
- electronic health record
- reactive oxygen species
- pi k akt
- binding protein
- nlrp inflammasome
- single cell
- big data
- high glucose
- heat shock protein
- mesenchymal stem cells
- stress induced
- endothelial cells
- endoplasmic reticulum
- copy number
- machine learning
- dna methylation
- dna binding
- cell therapy