Mutations in LR RK2(Leucine rich repeat kinase 2)are a major cause of Parkinson’s disease(PD).We and others reported recently that expression of the pathogenic gain-of-function mutant form of LRRK2,LRRK2 G2019S,induc...Mutations in LR RK2(Leucine rich repeat kinase 2)are a major cause of Parkinson’s disease(PD).We and others reported recently that expression of the pathogenic gain-of-function mutant form of LRRK2,LRRK2 G2019S,induc-es mitochondrial fi ssion in neurons through DLP1.Here we provide evidence that expression of LRRK2 G2019S stimulates mitochondria loss or mitophagy.We have char-acterized several LRRK2 interacting proteins and found that LRRK2 interacts with ULK1 which plays an essential role in autophagy.Knockdown of either ULK1 or DLP1 expression with shRNAs suppresses LRRK2 G2019S expression-induced mitochondrial clearance,suggesting that LRRK2 G2019S expression induces mitochondrial fi ssion through DLP1 followed by mitophagy via an ULK1 dependent pathway.In addition to ULK1,we found that LRRK2 interacts with the endogenous MKK4/7,JIP3 and coordinates with them in the activation of JNK signaling.Interestingly,LRRK2 G2019S-induced loss of mitochon-dria can also be suppressed by 3 different JNK inhibitors,implying the involvement of the JNK pathway in the path-ogenic mechanism of mutated LRRK2.Thus our fi ndings may provide an insight into the complicated pathogenesis of PD as well as some clues to the development of novel therapeutic strategies.展开更多
基金the Chinese Academy of Sciences(XDA01010105)the National Natural Science Foundation of China(Grant Nos.30725007,31271156 and 31270826)National Basic Research Program(973 Program)(No.2012CB517904).
文摘Mutations in LR RK2(Leucine rich repeat kinase 2)are a major cause of Parkinson’s disease(PD).We and others reported recently that expression of the pathogenic gain-of-function mutant form of LRRK2,LRRK2 G2019S,induc-es mitochondrial fi ssion in neurons through DLP1.Here we provide evidence that expression of LRRK2 G2019S stimulates mitochondria loss or mitophagy.We have char-acterized several LRRK2 interacting proteins and found that LRRK2 interacts with ULK1 which plays an essential role in autophagy.Knockdown of either ULK1 or DLP1 expression with shRNAs suppresses LRRK2 G2019S expression-induced mitochondrial clearance,suggesting that LRRK2 G2019S expression induces mitochondrial fi ssion through DLP1 followed by mitophagy via an ULK1 dependent pathway.In addition to ULK1,we found that LRRK2 interacts with the endogenous MKK4/7,JIP3 and coordinates with them in the activation of JNK signaling.Interestingly,LRRK2 G2019S-induced loss of mitochon-dria can also be suppressed by 3 different JNK inhibitors,implying the involvement of the JNK pathway in the path-ogenic mechanism of mutated LRRK2.Thus our fi ndings may provide an insight into the complicated pathogenesis of PD as well as some clues to the development of novel therapeutic strategies.
