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.
Mol Psychiatry. 2021 Jul;26(7):2721-2739. doi: 10.1038/s41380-021-01050-z. Epub 2021 Mar 4.
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.
功能失调的线粒体是帕金森病 (PD) 的特征。因此，揭示病因分子对于疾病的早期诊断和治疗至关重要，特别是对于特发性形式的疾病。本研究提出 18kDa 转位蛋白 (TSPO) 就是其中之一。无论是在体外还是体内数据都表明，表型模拟 PD 的神经毒素会增加 TSPO，以增强细胞氧化应激、对多巴胺诱导的细胞死亡的易感性，以及抑制泛素依赖性线粒体自噬。TSPO 放大细胞外信号调节激酶 1 和 2 (ERK1/2) 信号，形成正反馈，从而抑制转录因子 EB (TFEB) 和溶酶体的控制产生。最后，转录组的遗传变异证实，TSPO 在神经毒性过程中改变自噬溶酶体途径是必需的。
