title: Apoptotic mechanisms in mutant LRRK2-mediated cell death.
abstract: Mutations in the gene coding for leucine-rich repeat kinase 2 (LRRK2) cause autosomal-dominant Parkinson's disease. The pathological mutations have been associated with an increase of LRRK2 kinase activity, although its physiological substrates have not been identified yet. The data we report here demonstrate that disease-associated mutant LRRK2 cell toxicity is due to mitochondria-dependent apoptosis. Transient transfection of mutant LRRK2 leads to neuronal death with clear apoptotic signs. Soluble caspase inhibitors or the genetic ablation of Apaf1 protects cells from apoptotic death. Moreover, we explored the function of two protein domains in LRRK2 (LRR and WD40) and demonstrate that the lack of these protein domains has a protective effect on mitochondria dysfunctions induced by mutant LRRK2.
authors.affiliation: Department of Physiological, Biochemical, and Cell Science, University of Sassari, Via Muroni 25, 07100 Sassari,Italy.
authors.forename: Ciro
authors.initials: C
authors.lastname: Iaccarino
authors.forename: Claudia
authors.initials: C
authors.lastname: Crosio
authors.forename: Carmine
authors.initials: C
authors.lastname: Vitale
authors.forename: Giovanna
authors.initials: G
authors.lastname: Sanna
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Carrì
authors.forename: Paolo
authors.initials: P
authors.lastname: Barone
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D053477:Apoptotic Protease-Activating Factor 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008928:Mitochondria / Q000235:genetics / Q000473:pathology; D009474:Neurons / Q000473:pathology; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000235:genetics
chemical_list: C506592:APAF1 protein, human; D053477:Apoptotic Protease-Activating Factor 1; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases