Abstract
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.
Highlights
Prevalence of psychiatric symptoms in primary mitochondrial diseases are common [1, 2] and debilitating [3]
Based on the data collected, a heat map representing the binding of the radiolabelled, high-affinity [16, 29] Translocator Protein (TSPO) ligand [11C]PBR28 was generated (Fig. 1A). This effect was quantified via biodistribution analysis (Fig. 1B), indicating a marked upregulation of [11C]PBR28 uptake in the brains of 6OHDA-injected animals when compared to the shaminjected group
In order to test if dopaminergic neurons can upregulate TSPO following treatment with neurotoxins, we carried out an immunohistological analysis of coronal brain sections of 6-OHDAtreated rats (n = 3)
Summary
Prevalence of psychiatric symptoms in primary mitochondrial diseases are common [1, 2] and debilitating [3]. Secondary mitochondrial diseases are affected, and Parkinsonism is a vastly acknowledged example [4,5,6,7]. One useful tool to insight those and stratify patients from a mitochondrial perspective is the Translocator Protein (TSPO) [8, 9]. This multidrug-binding protein, which is resident on the Outer Mitochondrial Membrane (OMM), has been studied for over two decades as a diagnostic marker of neurotrauma and target for anxiolytic therapy [10, 11]. Evidence demonstrating the increased TSPO ligand binding in PD patients [12] made us query whether the protein had a causal role in the mitochondrial
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