PINK1/PARKIN signalling in neurodegeneration and neuroinflammation
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REVIEW
PINK1/PARKIN signalling in neurodegeneration and neuroinflammation Peter M. J. Quinn1,2, Paula I. Moreira3,4,5, António Francisco Ambrósio4,6,7,8 and C. Henrique Alves4,6,7,8*
Abstract Mutations in the PTEN-induced kinase 1 (PINK1) and Parkin RBR E3 ubiquitin-protein ligase (PARKIN) genes are associated with familial forms of Parkinson’s disease (PD). PINK1, a protein kinase, and PARKIN, an E3 ubiquitin ligase, control the specific elimination of dysfunctional or superfluous mitochondria, thus fine-tuning mitochondrial network and preserving energy metabolism. PINK1 regulates PARKIN translocation in impaired mitochondria and drives their removal via selective autophagy, a process known as mitophagy. As knowledge obtained using different PINK1 and PARKIN transgenic animal models is being gathered, growing evidence supports the contribution of mitophagy impairment to several human pathologies, including PD and Alzheimer’s diseases (AD). Therefore, therapeutic interventions aiming to modulate PINK1/PARKIN signalling might have the potential to treat these diseases. In this review, we will start by discussing how the interplay of PINK1 and PARKIN signalling helps mediate mitochondrial physiology. We will continue by debating the role of mitochondrial dysfunction in disorders such as amyotrophic lateral sclerosis, Alzheimer’s, Huntington’s and Parkinson’s diseases, as well as eye diseases such as age-related macular degeneration and glaucoma, and the causative factors leading to PINK1/PARKIN-mediated neurodegeneration and neuroinflammation. Finally, we will discuss PINK1/PARKIN gene augmentation possibilities with a particular focus on AD, PD and glaucoma. Keywords: PINK1, PARKIN, Mitophagy, Neurodegeneration, Alzheimer’s disease, Parkinson’s disease Background Mitochondria, first discovered in the late 1 9th century, are considered key for cellular bioenergetics [1, 2]. They consist of a double membrane with an intermembrane space. The inner membrane forms folds called cristae which provide an increased surface area for chemical and redox reactions to take place [3–5]. Mitochondria produce the majority of cellular adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS). The protein complexes (cI-IV) of the respiratory chain transfer electrons from NADH and FADH2 (provided by the Krebs cycle) to molecular O2, a process also known as the electron transport chain (ETC). The ETC creates *Correspondence: [email protected] 6 Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal Full list of author information is available at the end of the article
a membrane potential (ΔΨm) across the mitochondrial inner membrane by pumping protons from the mitochondrial matrix to the intermembrane space, thus creating a high concentration of protons in the intermembrane space and a low concentration in the mitochondrial matrix. Subsequently, along this chemiosmotic gradient, the protons move back into the mitochondrial matrix,
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