Neurodegenerative Loss of Mitochondrial Quality via the 18kDa Protein TSPO

Abstract

The 18kDa Translocator Protein (TSPO), is a nuclear-encoded protein residing on the outer mitochondrial membrane and linked to a variety of pathological conditions. Traditionally a target of pharmacological agents, its ability to efficiently signal cellular stress has been employed in diagnostic protocols of neuroinflammation1. Recently, breakthroughs on its role in mitochondrial physiology and metabolism, including the negative regulation of mitophagy, have provided evidences for its mechanistic role as stress-response adaptive element in pathophyioslogy. In previous studies, we demonstrated that TSPO is able to impair Parkin-mediated mitophagy via a Reactive Oxygen Species (ROS)-dependent mechanism2 and exploited in glutamate-induced excitotoxicity3. Using ex-vivo and in vitro models of Sporadic Parkinsonism, we now find that TSPO plays part in chronic damage associated with dopaminergic neurons’ demise. Our results suggest that, downstream of the ERK1/2 pathway, Parkinson's disease (PD) toxins induce a sustained upregulation of TSPO, which enacts a programme of mitochondrial signalling adaptation and impairment of mitochondria-targeted autophagy pivotal to cellular degeneration. All this makes of TSPO a pro-pathological candidate protein in PD, by impairing both mitochondrial quality control and signalling pathways of retrograde communications. The molecular determinants of this will be discussed and so the pharmacologically means4 to revert the phenotype by targeting TSPO. 1. Gatliff J and Campanella M. Biochem J. 2016 Jan 15;473(2):107-2. 2. Gatliff, et al. Autophagy 2014 Dec 2;10(12):2279-96. 3. Gatliff J, East D, et al. Cell Death Dis. 2017 Jun 22;8(6):e2896. 4. Georgakopoulos ND et al. Nat Chem Biol. 2017 Jan 19;13(2):136-146.