Mitochondrial E3 Ubiquitin Ligase Parkin: Relationships with Other Causal Proteins in Familial Parkinson's Disease and Its Substrate-Involved Mouse Experimental Models.

Satoru Torii,Tatsushi Yoshida,Shuya Kasai,Shigeomi Shimizu,Ken-Ichi Yasumoto

doi:10.3390/ijms21041202

Abstract

Parkinson’s disease (PD) is a common neurodegenerative disorder. Recent identification of genes linked to familial forms of PD has revealed that post-translational modifications, such as phosphorylation and ubiquitination of proteins, are key factors in disease pathogenesis. In PD, E3 ubiquitin ligase Parkin and the serine/threonine-protein kinase PTEN-induced kinase 1 (PINK1) mediate the mitophagy pathway for mitochondrial quality control via phosphorylation and ubiquitination of their substrates. In this review, we first focus on well-characterized PINK1 phosphorylation motifs. Second, we describe our findings concerning relationships between Parkin and HtrA2/Omi, a protein involved in familial PD. Third, we describe our findings regarding inhibitory PAS (Per/Arnt/Sim) domain protein (IPAS), a member of PINK1 and Parkin substrates, involved in neurodegeneration during PD. IPAS is a dual-function protein involved in transcriptional repression of hypoxic responses and the pro-apoptotic activities.

Highlights

Parkinson’s disease (PD) is the second most common neurodegenerative disease and is characterized by progressive resting tremors, rigidity, bradykinesia, gait disturbances, postural instability, and dementia [1,2]
Considering that inhibitory PAS (Per/Arnt/Sim) domain protein (IPAS) is induced by oxidative stress in neural tissues and that the pro-apoptotic activity of mitochondrial IPAS is activated by oxidative stress, we suggest a relationship between IPAS-induced neural cell death and neurodegenerative disorders
Some studies demonstrate that MK2-deficient mice are resistant to MPTP-induced neurodegeneration in the substantia nigra pars compacta (SNpc) when compared with WT mice [72] and that the selective activation of p38 signaling by MPTP treatment occurs in dopaminergic neurons within the SNpc [73]

Summary

Introduction

Parkinson’s disease (PD) is the second most common neurodegenerative disease and is characterized by progressive resting tremors, rigidity, bradykinesia, gait disturbances, postural instability, and dementia [1,2]. Mutations of park genes including Parkin, PINK1, HtrA2/Omi and CHCHD2 are directly involved in mitochondrial dysfunction [12,13,14,15]. Increasing numbers of studies using CCCP treatment have investigated the substrates of PINK1 phosphorylation, including Miro1/Rhot1 [33], PINK1 (autophosphorylation) [34], Parkin [20,21], Mitofusin 2 [35], Int. J.

Results

Conclusion