Apoptotic mechanisms in mutant LRRK2-mediated cell death
- Resource Type
- Authors
- Paolo Barone; Maria Teresa Carrì; Carmine Vitale; Claudia Crosio; Ciro Iaccarino; Giovanna Sanna
- Source
- Human molecular genetics. 16(11)
- Subject
- Protein Structure
Programmed cell death
Mutant
Apoptosis
Biology
Protein Serine-Threonine Kinases
medicine.disease_cause
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
Cell Line
Cell Line, Tumor
Genetics
medicine
Humans
APAF1
Settore BIO/10
Kinase activity
Apoptotic Protease-Activating Factor 1
Parkinson Disease
Neurons
Mitochondria
Protein-Serine-Threonine Kinases
Protein Structure, Tertiary
Molecular Biology
Genetics (clinical)
Mutation
Tumor
General Medicine
Transfection
LRRK2
nervous system diseases
Cell biology
Tertiary
- Language
- ISSN
- 0964-6906
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.