Mitochondrial dysfunction and mitophagy defect triggered by heterozygous GBA mutations

Autophagy
Hongyu LiGuomei Tang

Abstract

Heterozygous mutations in GBA, the gene encoding the lysosomal enzyme glucosylceramidase beta/β-glucocerebrosidase, comprise the most common genetic risk factor for Parkinson disease (PD), but the mechanisms underlying this association remain unclear. Here, we show that in GbaL444P/WT knockin mice, the L444P heterozygous Gba mutation triggers mitochondrial dysfunction by inhibiting autophagy and mitochondrial priming, two steps critical for the selective removal of dysfunctional mitochondria by autophagy, a process known as mitophagy. In SHSY-5Y neuroblastoma cells, the overexpression of L444P GBA impeded mitochondrial priming and autophagy induction when endogenous lysosomal GBA activity remained intact. By contrast, genetic depletion of GBA inhibited lysosomal clearance of autophagic cargo. The link between heterozygous GBA mutations and impaired mitophagy was corroborated in postmortem brain tissue from PD patients carrying heterozygous GBA mutations, where we found increased mitochondrial content, mitochondria oxidative stress and impaired autophagy. Our findings thus suggest a mechanistic basis for mitochondrial dysfunction associated with GBA heterozygous mutations. Abbreviations: AMBRA1: autophagy/beclin 1 regulator 1; B...Continue Reading

References

Jul 29, 2006·Autophagy·Sara Rodriguez-EnriquezJohn J Lemasters
Jun 21, 2007·The Journal of Biological Chemistry·Serhiy PankivTerje Johansen
Dec 1, 2007·Proceedings of the National Academy of Sciences of the United States of America·Rachel L SchweersPaul A Ney
Dec 21, 2007·Lancet Neurology·Anthony H V Schapira
Jan 31, 2008·Proceedings of the National Academy of Sciences of the United States of America·Angela C PooleLeo J Pallanck
Jul 18, 2008·Current Protocols in Neuroscience·Mandar A ArasElias Aizenman
Oct 22, 2008·Methods : a Companion to Methods in Enzymology·Denis M Medeiros
Nov 26, 2008·The Journal of Cell Biology·Derek NarendraRichard J Youle
Mar 3, 2009·Molecular Cell·Vladimir KirkinTerje Johansen
Sep 8, 2009·Biochimica Et Biophysica Acta·Konstanze F Winklhofer, Christian Haass
Oct 23, 2009·The New England Journal of Medicine·E SidranskyS G Ziegler
Dec 17, 2009·EMBO Reports·Ivana NovakIvan Dikic
Nov 26, 2010·Blood Cells, Molecules & Diseases·Inna Bendikov-BarMia Horowitz
Nov 26, 2010·Autophagy·Hong-Min NiWen-Xing Ding
Dec 24, 2010·Nature Reviews. Molecular Cell Biology·Richard J Youle, Derek P Narendra
Mar 2, 2011·The EMBO Journal·Flavie StrappazzonFrancesco Cecconi
Jul 7, 2011·Proceedings of the National Academy of Sciences of the United States of America·S Pablo SardiLamya S Shihabuddin
Jul 15, 2011·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Cindy Van HumbeeckWim Vandenberghe
Aug 27, 2011·Chemistry & Biology·Hiroyuki KatayamaAtsushi Miyawaki
Sep 14, 2011·Methods in Molecular Biology·Jianhui ZhuCharleen T Chu
Nov 15, 2011·Antioxidants & Redox Signaling·Ivana Novak
Jan 10, 2012·Human Molecular Genetics·Xinglong WangXiongwei Zhu
Mar 27, 2012·Journal of Cell Science·Seok Min Jin, Richard J Youle
May 25, 2012·Human Mutation·Inna Bendikov-Bar, Mia Horowitz
Oct 5, 2012·Annals of Neurology·Matthew E GeggAnthony H V Schapira
Oct 20, 2012·Lancet Neurology·Ellen Sidransky, Grisel Lopez
Oct 27, 2012·Neurochemistry International·Michael W J CleeterAnthony Henry Schapira
Nov 6, 2012·Cold Spring Harbor Perspectives in Biology·Derek NarendraRichard Youle
Nov 20, 2012·Trends in Cell Biology·Kie ItohHiromi Sesaki
Jan 4, 2013·Molecular Biology of the Cell·Oliver C LosónDavid C Chan
Jan 22, 2013·Neurobiology of Disease·Guomei TangDavid Sulzer
Jan 31, 2013·Molecular Neurobiology·Stephen Mullin, Anthony Schapira
Apr 17, 2013·JAMA Neurology·Michael A NallsEllen Sidransky
Jun 5, 2013·Cold Spring Harbor Perspectives in Biology·Alexander M van der BliekSumihiro Kawajiri
Aug 3, 2013·Cell Cycle·Francesca Nazio, Francesco Cecconi
Nov 2, 2013·Journal of the American Society of Nephrology : JASN·Ling LiFangming Lin

❮ Previous
Next ❯

Citations

Jun 13, 2019·Current Opinion in Neurology·Emory RyanEllen Sidransky
May 3, 2019·CNS Neuroscience & Therapeutics·Yan WangBingwei Lu
Jan 9, 2020·Movement Disorders : Official Journal of the Movement Disorder Society·Shaozhen JiPiu Chan
Jan 7, 2020·Experimental Neurobiology·So Yeong CheonJong Eun Lee
May 21, 2020·Molecular Neurobiology·Aida ZuluetaMarco Trinchera
Nov 22, 2019·Aging·Constanza MorénAnthony Henry Vernon Schapira
Aug 28, 2020·Expert Opinion on Investigational Drugs·Margherita FabbriOlivier Rascol
Jul 10, 2019·International Journal of Molecular Sciences·Rossella Indellicato, Marco Trinchera
Dec 1, 2019·Molecular Brain·Bilal R MalikOwen M Peters
Oct 5, 2019·Oxidative Medicine and Cellular Longevity·Ruru Li, Jianzong Chen
Jul 18, 2020·International Journal of Molecular Sciences·Shani BlumenreichAnthony H Futerman
Jun 12, 2019·Cells·Marie-Laure ArotcarenaBenjamin Dehay
May 7, 2020·Frontiers in Aging Neuroscience·Micol AvenaliSilvia Cerri
Jan 8, 2020·Metabolites·Gabriele DossiMario Rango
Sep 10, 2020·Frontiers in Neuroscience·Nicholas G Norwitz, Henry Querfurth
Sep 27, 2019·Frontiers in Cell and Developmental Biology·Adina Maria PalhegyiSovan Sarkar
Nov 17, 2019·International Journal of Molecular Sciences·Kai-Jung LinTsu-Kung Lin
Nov 22, 2020·Movement Disorders : Official Journal of the Movement Disorder Society·Patricia García-SanzRosario Moratalla
Dec 30, 2020·The Journal of Biological Chemistry·Emily H ClarkThomas Briston
Nov 24, 2020·Oxidative Medicine and Cellular Longevity·Natalia Jimenez-Moreno, Jon D Lane
Dec 18, 2020·Frontiers in Cell and Developmental Biology·Tsu-Kung LinTzu-Jou Wang
Jan 8, 2021·The Journal of Biological Chemistry·Emily H ClarkThomas Briston
Feb 18, 2020·Journal of Molecular Biology·Xu HouWolfdieter Springer
Dec 17, 2020·Trends in Biochemical Sciences·Ana Belen MalpartidaBrent J Ryan
Apr 24, 2021·Acta Physiologica·Hongke LuoNuo Sun
May 12, 2021·Neuropathology and Applied Neurobiology·Lucie ValekIrmgard Tegeder
Oct 15, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Jason Thomas DuskeyBarbara Ruozi
Jun 17, 2021·Molecular Aspects of Medicine·Britney N Lizama, Charleen T Chu
Jul 25, 2021·International Journal of Molecular Sciences·Milena FaisCiro Iaccarino

❮ Previous
Next ❯

Datasets Mentioned

BETA
GM03524
ND31360
GM00878

Methods Mentioned

BETA
GTPase
transgenic
gene knockout
ubiquitination
density gradient centrifugation
Assay

Software Mentioned

GraphPad Prism
ImageJ
Image J
ImageJ Mito - Morphology
Gen5

Related Concepts

Related Feeds

BCL-2 Family Proteins

BLC-2 family proteins are a group that share the same homologous BH domain. They play many different roles including pro-survival signals, mitochondria-mediated apoptosis and removal or damaged cells. They are often regulated by phosphorylation, affecting their catalytic activity. Here is the latest research on BCL-2 family proteins.

Autophagy & Aging: Inhibitors

The feed focuses on the role of nuclear export inhibitors and their effect on autophagy and the aging process.

Parkinson's Disease & Autophagy

Autophagy leads to degradation of damaged proteins and organelles by the lysosome. Impaired autophagy has been implicated in several diseases. Here is the role of autophagy in Parkinson’s disease.

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.

Parkinson's Disease & Autophagy (MDS)

Autophagy leads to degradation of damaged proteins and organelles by the lysosome. Impaired autophagy has been implicated in several diseases. Here is the role of autophagy in Parkinson’s disease.

Autophagy & Model Organisms

Autophagy is a cellular process that allows degradation by the lysosome of cytoplasmic components such as proteins or organelles. Here is the latest research on autophagy & model organisms