Apoptotic mechanisms in mutant LRRK2-mediated cell death.
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.
Iaccarino
Ciro
C
Department of Physiological, Biochemical, and Cell Science, University of Sassari, Via Muroni 25, 07100 Sassari,Italy.
Crosio
Claudia
C
Vitale
Carmine
C
Sanna
Giovanna
G
Carrì
Maria Teresa
MT
Barone
Paolo
P
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
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