CDK5-Mediated Phosphorylation-Dependent Ubiquitination and Degradation of E3 Ubiquitin Ligases GP78 Accelerates Neuronal Death in Parkinson's Disease

Molecular Neurobiology
Qingzhi WangBo Tian

Abstract

The molecular mechanisms responsible for the loss of dopaminergic neurons in Parkinson's disease (PD) remain obscure. Loss of function of E3 ubiquitin ligases is associated with mitochondria dysfunction, dysfunction of protein degradation, and α-synuclein aggregation, which are major contributors to neurodegeneration in PD. Recent research has thus focused on E3 ubiquitin ligase glycoprotein 78 (GP78); however, the role of GP78 in PD pathogenesis remains unclear. Notably, cyclin-dependent kinase 5 (CDK5) controls multiple cellular events in postmitotic neurons, and CDK5 activity has been implicated in the pathogenesis of PD. Thus, we addressed the relationship between CDK5 and GP78 in MPTP-based PD models. We found that GP78 expression is decreased in MPTP-based cellular and animal PD models, and CDK5 directly phosphorylated GP78 at Ser516, which promoted the ubiquitination and degradation of GP78. Importantly, overexpression of GP78 or interference of GP78 Ser516 phosphorylation protected neurons against MPP+-induced cell death. Thus, our research reveals that the CDK5-GP78 pathway is involved in the pathogenesis of PD and could be a novel candidate drug target for the treatment of PD.

References

Jun 1, 1975·European Journal of Biochemistry·H KüntzelD E Leister
Sep 26, 1995·Proceedings of the National Academy of Sciences of the United States of America·S Lahav-BaratzA Hershko
Sep 18, 2001·Annals of Neurology·M FarrerJ W Langston
Nov 29, 2001·Proceedings of the National Academy of Sciences of the United States of America·S FangA M Weissman
May 24, 2003·Brain : a Journal of Neurology·Naheed L KhanNiall Quinn
Nov 1, 2003·Science·Ted M Dawson, Valina L Dawson
Jun 15, 2005·Annual Review of Biochemistry·Mark R Cookson
Jul 19, 2005·Annual Review of Neuroscience·Darren J MooreTed M Dawson
Jan 13, 2006·Proceedings of the National Academy of Sciences of the United States of America·Bo ChenAllan M Weissman
Oct 24, 2007·Seminars in Cell & Developmental Biology·Zlatka KostovaAllan M Weissman
Nov 27, 2007·Nature Medicine·Yien Che TsaiAllan M Weissman
Sep 27, 2008·The EMBO Journal·Carolina MaestreAngeles Almeida
Feb 19, 2009·Proceedings of the National Academy of Sciences of the United States of America·Wei LiYihong Ye
Aug 8, 2009·Human Molecular Genetics·Zheng YingGuanghui Wang
Sep 29, 2009·Trends in Neurosciences·Sebastian JessbergerDiane C Lagace
Feb 4, 2010·PLoS Biology·Rachel Jones
Oct 22, 2010·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Diego PiedrahitaGloria Patricia Cardona-Gómez
Nov 29, 2011·Nature Cell Biology·John C ChristiansonRon R Kopito
Dec 23, 2011·Trends in Cell Biology·Zelda H Cheung, Nancy Y Ip
Feb 22, 2013·Molecular Biology of the Cell·Min FuIvan R Nabi
Aug 1, 2015·Molecular Neurobiology·Shu-Lei LiuJin-Tai Yu
Feb 9, 2016·Movement Disorders : Official Journal of the Movement Disorder Society·Pei ZhangBo Tian

❮ Previous
Next ❯

Methods Mentioned

BETA
transfections
Ubiquitination
immunoprecipitation
co-immunoprecipitation

Software Mentioned

GPS
ScanSite

Related Concepts

Related Feeds

Cell Checkpoints & Regulators

Cell cycle checkpoints are a series of complex checkpoint mechanisms that detect DNA abnormalities and ensure that DNA replication and repair are complete before cell division. They are primarily regulated by cyclins, cyclin-dependent kinases, and the anaphase-promoting complex/cyclosome. Here is the latest research.

Alpha-Synuclein Aggregation

Alpha-synucleins are small proteins that are believed to restrict the mobility of synpatic vesicles and inhibit neurotransmitter release. Aggregation of these proteins have been linked to several types of neurodegenerative diseases including dementia with Lewy bodies and Parkinson's disease. Here is the latest research on α-synuclein aggregation.

Cell Cycle Control & Proteolysis

Key regulators of cell cycle, including cyclins, cyclin dependent kinase inhibitors, DNA replication factors, are controlled by proteolysis. Discover the latest research on cell cycle control and proteolysis.

Alpha-Synuclein Aggregation (MDS)

Alpha-synucleins are small proteins that are believed to restrict the mobility of synpatic vesicles and inhibit neurotransmitter release. Aggregation of these proteins have been linked to several types of neurodegenerative diseases including dementia with Lewy bodies and Parkinson's disease. Here is the latest research on α-synuclein aggregation.