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Apoptotic mechanisms in mutant LRRK2-mediated cell death

2007; Oxford University Press; Volume: 16; Issue: 11 Linguagem: Inglês

10.1093/hmg/ddm080

1460-2083

Ciro Iaccarino, Claudia Crosio, Carmine Vitale, Giovanna Sanna, Maria Teresa Carrı̀, Paolo Barone,

Plant Gene Expression Analysis

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.