ABSTRACT
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 gainof-function mutant form of LRRK2, LRRK2 G2019S, induces mitochondrial fission in neurons through DLP1. Here we provide evidence that expression of LRRK2 G2019S stimulates mitochondria loss or mitophagy. We have characterized 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 fission 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 mitochondria can also be suppressed by 3 different JNK inhibitors, implying the involvement of the JNK pathway in the pathogenic mechanism of mutated LRRK2. Thus our findings may provide an insight into the complicated pathogenesis of PD as well as some clues to the development of novel therapeutic strategies.
Subject(s)
Humans , Amino Acid Substitution , Autophagosomes , Metabolism , Pathology , Autophagy-Related Protein-1 Homolog , Chemistry , Genetics , Metabolism , GTP Phosphohydrolases , Genetics , Metabolism , Gene Knockdown Techniques , HeLa Cells , Intracellular Signaling Peptides and Proteins , Chemistry , Genetics , Metabolism , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 , Chemistry , Genetics , Metabolism , MAP Kinase Signaling System , Microtubule-Associated Proteins , Genetics , Metabolism , Mitophagy , Genetics , Physiology , Mitochondrial Proteins , Genetics , Metabolism , Mutant Proteins , Chemistry , Genetics , Metabolism , Mutation , Parkinson Disease , Genetics , Metabolism , Pathology , Protein Interaction Domains and Motifs , Recombinant Proteins , Chemistry , Genetics , MetabolismABSTRACT
Autophagy contributes to the pathology of various neurodegenerative conditions.Rapamycin,an agent against Candida albicans or immunosuppressive,was found to be effective against tumor.Furthermore,it also induces autophagy by inactivating the protein mammalian target of rapamycin(mTOR),FKBP and VMP1,thus could offer a tractable therapeutic agent for neurodegenerative diseases.