The Enzymatic Core of the Parkinson's Disease-Associated Protein LRRK2 Impairs Mitochondrial Biogenesis in Aging Yeast.
The Enzymatic Core of the Parkinson's Disease-Associated Protein LRRK2 Impairs Mitochondrial Biogenesis in Aging Yeast.
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DOI：
10.3389/fnmol.2018.00205
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发表时间：
2018
影响因子：
4.8
通讯作者：
Büttner S
中科院分区：
文献类型：
--
作者：
Aufschnaiter A;Kohler V;Walter C;Tosal-Castano S;Habernig L;Wolinski H;Keller W;Vögtle FN;Büttner S
Mitochondrial dysfunction is a prominent trait of cellular decline during aging and intimately linked to neuronal degeneration during Parkinson’s disease (PD). Various proteins associated with PD have been shown to differentially impact mitochondrial dynamics, quality control and function, including the leucine-rich repeat kinase 2 (LRRK2). Here, we demonstrate that high levels of the enzymatic core of human LRRK2, harboring GTPase as well as kinase activity, decreases mitochondrial mass via an impairment of mitochondrial biogenesis in aging yeast. We link mitochondrial depletion to a global downregulation of mitochondria-related gene transcripts and show that this catalytic core of LRRK2 localizes to mitochondria and selectively compromises respiratory chain complex IV formation. With progressing cellular age, this culminates in dissipation of mitochondrial transmembrane potential, decreased respiratory capacity, ATP depletion and generation of reactive oxygen species. Ultimately, the collapse of the mitochondrial network results in cell death. A point mutation in LRRK2 that increases the intrinsic GTPase activity diminishes mitochondrial impairment and consequently provides cytoprotection. In sum, we report that a downregulation of mitochondrial biogenesis rather than excessive degradation of mitochondria underlies the reduction of mitochondrial abundance induced by the enzymatic core of LRRK2 in aging yeast cells. Thus, our data provide a novel perspective for deciphering the causative mechanisms of LRRK2-associated PD pathology.
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影响因子：
4.2
作者：
Heckman MG;Elbaz A;Soto-Ortolaza AI;Serie DJ;Aasly JO;Annesi G;Auburger G;Bacon JA;Boczarska-Jedynak M;Bozi M;Brighina L;Chartier-Harlin MC;Dardiotis E;Destée A;Ferrarese C;Ferraris A;Fiske B;Gispert S;Hadjigeorgiou GM;Hattori N;Ioannidis JP;Jasinska-Myga B;Jeon BS;Kim YJ;Klein C;Kruger R;Kyratzi E;Lin CH;Lohmann K;Loriot MA;Lynch T;Mellick GD;Mutez E;Opala G;Park SS;Petrucci S;Quattrone A;Sharma M;Silburn PA;Sohn YH;Stefanis L;Tadic V;Tomiyama H;Uitti RJ;Valente EM;Vassilatis DK;Vilariño-Güell C;White LR;Wirdefeldt K;Wszolek ZK;Wu RM;Xiromerisiou G;Maraganore DM;Farrer MJ;Ross OA;Genetic Epidemiology Of Parkinson's Disease (GEO-PD) Consortium
通讯作者：
Genetic Epidemiology Of Parkinson's Disease (GEO-PD) Consortium
影响因子：
17.1
作者：
Cooper O;Seo H;Andrabi S;Guardia-Laguarta C;Graziotto J;Sundberg M;McLean JR;Carrillo-Reid L;Xie Z;Osborn T;Hargus G;Deleidi M;Lawson T;Bogetofte H;Perez-Torres E;Clark L;Moskowitz C;Mazzulli J;Chen L;Volpicelli-Daley L;Romero N;Jiang H;Uitti RJ;Huang Z;Opala G;Scarffe LA;Dawson VL;Klein C;Feng J;Ross OA;Trojanowski JQ;Lee VM;Marder K;Surmeier DJ;Wszolek ZK;Przedborski S;Krainc D;Dawson TM;Isacson O
通讯作者：
Isacson O
影响因子：
5.4
作者：
Klein, Christine;Westenberger, Ana
通讯作者：
Westenberger, Ana
影响因子：
--
作者：
Buschlen, S;Amillet, JM;Bolotin-Fukuhara, M
通讯作者：
Bolotin-Fukuhara, M
影响因子：
11.2
作者：
Biskup, Saskia;Moore, Darren J.;Dawson, Valina L.
通讯作者：
Dawson, Valina L.