PINK1/Parkin Mediated Mitophagy, Ca2+ Signalling, and ER-Mitochondria Contacts in Parkinson's Disease.

Lucia Barazzuol,Tito Calì,Flavia Giamogante,Marisa Brini

doi:10.3390/ijms21051772

Abstract

Endoplasmic reticulum (ER)–mitochondria contact sites are critical structures for cellular function. They are implicated in a plethora of cellular processes, including Ca2+ signalling and mitophagy, the selective degradation of damaged mitochondria. Phosphatase and tensin homolog (PTEN)-induced kinase (PINK) and Parkin proteins, whose mutations are associated with familial forms of Parkinson’s disease, are two of the best characterized mitophagy players. They accumulate at ER–mitochondria contact sites and modulate organelles crosstalk. Alterations in ER–mitochondria tethering are a common hallmark of many neurodegenerative diseases including Parkinson’s disease. Here, we summarize the current knowledge on the involvement of PINK1 and Parkin at the ER–mitochondria contact sites and their role in the modulation of Ca2+ signalling and mitophagy.

Highlights

Parkinson’s disease (PD) is an incurable chronic progressive neurodegenerative disease affecting nearly 2% of the “over 50” population, with an approximate estimate of more than 6 million cases worldwide [1]. It is characterized by the preferential loss of dopaminergic neurons in the substantia nigra pars compacta, which results in progressive motor system malfunction, accompanied with the accumulation of proteinaceous aggregates, referred to as Lewy bodies (LB), in the remaining neurons of affected individuals [2]
Parkin and PINK1 have been shown to localize at the endoplasmic reticulum (ER)–mitochondria contact sites and to modulate the crosstalk between the two organelles [10]
The aim of this review is to summarize the literature concerning the PINK1 and Parkin role as multifunctional players in mitophagy and in ER–mitochondria tethering

Summary

Introduction

Parkinson’s disease (PD) is an incurable chronic progressive neurodegenerative disease affecting nearly 2% of the “over 50” population, with an approximate estimate of more than 6 million cases worldwide [1]. Genome-wide association studies have established 26 PD risk loci to date and, among the different PARK genes, those which encode α-synuclein (PARK1/4), Parkin (PARK2), PINK1 (phosphatase and tensin homolog (PTEN)-induced kinase 1—PARK6), DJ-1 (PARK7), LRRK2 (PARK8), and ATP13A2 (PARK9) have been deeply investigated Mutations in both LRRK2 and α-synuclein result in autosomal dominant inherited disease, whilst mutations in DJ-1, Parkin, PINK1, and ATP13A2 proteins give rise to autosomal recessive forms. Mice defective in autophagy/mitophagy have been shown to recapitulate a series of phenotypes resembling some PD features such as behavioural defects, reduction in coordinated movement, neuronal loss in the cerebral and cerebellar cortices, and accumulation of polyubiquitinated proteins as inclusion bodies [6,7] To this day, among the best characterized PD proteins are Parkin (an E3 ubiquitin ligase) and PINK1 (a serine/threonine kinase with a mitochondrial targeting sequence), whose mutations are the most common cause of recessive PD. The aim of this review is to summarize the literature concerning the PINK1 and Parkin role as multifunctional players in mitophagy and in ER–mitochondria tethering

Objectives

Findings

Conclusion