Biochemical properties of the kinase PINK1 as sensor protein for mitochondrial damage signalling

Cornelia Rüb; Nadja Schröder; Wolfgang Voos

doi:10.1042/bst20150005

Biochemical properties of the kinase PINK1 as sensor protein for mitochondrial damage signalling

Biochemical Society Transactions ◽

10.1042/bst20150005 ◽

2015 ◽

Vol 43 (2) ◽

pp. 287-291 ◽

Cited By ~ 7

Author(s):

Cornelia Rüb ◽

Nadja Schröder ◽

Wolfgang Voos

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Causative Factor ◽

Biochemical Properties ◽

Mitochondrial Damage ◽

Mitochondrial Functions ◽

Biochemical Mechanisms ◽

Autophagic Process ◽

Phosphatase And Tensin Homologue

Defects of mitochondrial functions have been implicated in many different human diseases, in particular neurodegenerative diseases. The kinase PINK1 [phosphatase and tensin homologue (PTEN)-induced kinase 1] has been identified as a crucial player in a specific damage signalling pathway, eliminating defective mitochondria by an autophagic process. Mutations in PINK1 have been shown to cause familial cases of Parkinson's disease. In this review, we summarize the biochemical mechanisms that underlie the association of PINK1 with mitochondria under normal and pathological conditions. This unconventional mitochondrial localization pathway is discussed in the context of the role of PINK1 as a sensor of mitochondrial damage and a causative factor in Parkinson's disease.

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Activation mechanisms of the E3 ubiquitin ligase parkin

Biochemical Journal ◽

10.1042/bcj20170476 ◽

2017 ◽

Vol 474 (18) ◽

pp. 3075-3086 ◽

Cited By ~ 24

Author(s):

Nikhil Panicker ◽

Valina L. Dawson ◽

Ted M. Dawson

Keyword(s):

Parkinson’S Disease ◽

Amino Acid ◽

Ubiquitin Ligase ◽

Recent Literature ◽

E3 Ubiquitin Ligase ◽

Mitochondrial Damage ◽

Cytosolic Protein ◽

Mitochondrial Functions ◽

Activation Mechanisms

Monogenetic, familial forms of Parkinson's disease (PD) only account for 5–10% of the total number of PD cases, but analysis of the genes involved therein is invaluable to understanding PD-associated neurodegenerative signaling. One such gene, parkin, encodes a 465 amino acid E3 ubiquitin ligase. Of late, there has been considerable interest in the role of parkin signaling in PD and in identifying its putative substrates, as well as the elucidation of the mechanisms through which parkin itself is activated. Its dysfunction underlies both inherited and idiopathic PD-associated neurodegeneration. Here, we review recent literature that provides a model of activation of parkin in the setting of mitochondrial damage that involves PINK1 (PTEN-induced kinase-1) and phosphoubiquitin. We note that neuronal parkin is primarily a cytosolic protein (with various non-mitochondrial functions), and discuss potential cytosolic parkin activation mechanisms.

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Expanding the role of proteasome homeostasis in Parkinson’s disease: beyond protein breakdown

Cell Death and Disease ◽

10.1038/s41419-021-03441-0 ◽

2021 ◽

Vol 12 (2) ◽

Cited By ~ 1

Author(s):

Mingxia Bi ◽

Xixun Du ◽

Qian Jiao ◽

Xi Chen ◽

Hong Jiang

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Clinical Intervention ◽

Great Majority ◽

Causative Factor ◽

Protein Accumulation ◽

Pathological Feature ◽

Homeostasis Regulation ◽

Disease Modifying Treatment

AbstractProteasome is the principal hydrolytic machinery responsible for the great majority of protein degradation. The past three decades have testified prominent advances about proteasome involved in almost every aspect of biological processes. Nonetheless, inappropriate increase or decrease in proteasome function is regarded as a causative factor in several diseases. Proteasome abundance and proper assembly need to be precisely controlled. Indeed, various neurodegenerative diseases including Parkinson’s disease (PD) share a common pathological feature, intracellular protein accumulation such as α-synuclein. Proteasome activation may effectively remove aggregates and prevent the neurodegeneration in PD, which provides a potential application for disease-modifying treatment. In this review, we build on the valuable discoveries related to different types of proteolysis by distinct forms of proteasome, and how its regulatory and catalytic particles promote protein elimination. Additionally, we summarize the emerging ideas on the proteasome homeostasis regulation by targeting transcriptional, translational, and post-translational levels. Given the imbalanced proteostasis in PD, the strategies for intensifying proteasomal degradation are advocated as a promising approach for PD clinical intervention.

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Role of Autophagy in Parkinson’s Disease

Current Medicinal Chemistry ◽

10.2174/0929867325666180226094351 ◽

2019 ◽

Vol 26 (20) ◽

pp. 3702-3718 ◽

Cited By ~ 22

Author(s):

Silvia Cerri ◽

Fabio Blandini

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Therapeutic Interventions ◽

Pharmacological Targets ◽

Potential Efficacy ◽

Low Toxicity ◽

Autophagic Process ◽

Chaperone Mediated Autophagy ◽

Neuronal Autophagy

Autophagy is an essential catabolic mechanism that delivers misfolded proteins and damaged organelles to the lysosome for degradation. Autophagy pathways include macroautophagy, chaperone-mediated autophagy and microautophagy, each involving different mechanisms of substrate delivery to lysosome. Defects of these pathways and the resulting accumulation of protein aggregates represent a common pathobiological feature of neurodegenerative disorders such as Alzheimer, Parkinson and Huntington disease. This review provides an overview of the role of autophagy in Parkinson’s disease (PD) by summarizing the most relevant genetic and experimental evidence showing how this process can contribute to disease pathogenesis. Given lysosomes take part in the final step of the autophagic process, the role of lysosomal defects in the impairment of autophagy and their impact on disease will also be discussed. A glance on the role of non-neuronal autophagy in the pathogenesis of PD will be included. Moreover, we will examine novel pharmacological targets and therapeutic strategies that, by boosting autophagy, may be theoretically beneficial for PD. Special attention will be focused on natural products, such as phenolic compounds, that are receiving increasing consideration due to their potential efficacy associated with low toxicity. Although many efforts have been made to elucidate autophagic process, the development of new therapeutic interventions requires a deeper understanding of the mechanisms that may lead to autophagy defects in PD and should take into account the multifactorial nature of the disease as well as the phenotypic heterogeneity of PD patients.

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