The LRRK2 inhibitor GSK2578215A induces protective autophagy in SH-SY5Y cells: involvement of Drp-1-mediated mitochondrial fission and mitochondrial-derived ROS signaling.

TitleThe LRRK2 inhibitor GSK2578215A induces protective autophagy in SH-SY5Y cells: involvement of Drp-1-mediated mitochondrial fission and mitochondrial-derived ROS signaling.
Publication TypeJournal Article
Year of Publication2014
AuthorsSaez-Atienzar, S, Bonet-Ponce, L, Blesa, JR, Romero, FJ, Murphy, MP, Jordan, J, Galindo, MF
JournalCell Death Dis
Volume5
Paginatione1368
Date Published2014 Aug 14
ISSN2041-4889
KeywordsAldehydes, Aminopyridines, Autophagy, Benzamides, Benzodiazepinones, Cell Line, Tumor, GTP Phosphohydrolases, Humans, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Microtubule-Associated Proteins, Mitochondria, Mitochondrial Dynamics, Mitochondrial Proteins, Organophosphorus Compounds, Oxidative Stress, Protein-Serine-Threonine Kinases, Pyrimidines, RNA Interference, RNA, Small Interfering, Signal Transduction, Ubiquinone
Abstract

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been associated with Parkinson's disease, and its inhibition opens potential new therapeutic options. Among the drug inhibitors of both wild-type and mutant LRRK2 forms is the 2-arylmethyloxy-5-subtitutent-N-arylbenzamide GSK257815A. Using the well-established dopaminergic cell culture model SH-SY5Y, we have investigated the effects of GSK2578215A on crucial neurodegenerative features such as mitochondrial dynamics and autophagy. GSK2578215A induces mitochondrial fragmentation of an early step preceding autophagy. This increase in autophagosome results from inhibition of fusion rather than increases in synthesis. The observed effects were shared with LRRK2-IN-1, a well-described, structurally distinct kinase inhibitor compound or when knocking down LRRK2 expression using siRNA. Studies using the drug mitochondrial division inhibitor 1 indicated that translocation of the dynamin-related protein-1 has a relevant role in this process. In addition, autophagic inhibitors revealed the participation of autophagy as a cytoprotective response by removing damaged mitochondria. GSK2578215A induced oxidative stress as evidenced by the accumulation of 4-hydroxy-2-nonenal in SH-SY5Y cells. The mitochondrial-targeted reactive oxygen species scavenger MitoQ positioned these species as second messengers between mitochondrial morphologic alterations and autophagy. Altogether, our results demonstrated the relevance of LRRK2 in mitochondrial-activated pathways mediating in autophagy and cell fate, crucial features in neurodegenerative diseases.

DOI10.1038/cddis.2014.320
Alternate JournalCell Death Dis
Citation Key10.1038/cddis.2014.320
PubMed ID25118928
PubMed Central IDPMC4454299
Grant ListMC_U105663142 / / Medical Research Council / United Kingdom