RESUMO
Parkinson's disease (PD) is a common neurodegenerative disorder. Disease symptoms correlate with the degeneration of dopaminergic neurons in substantia nigra pars compacta. A number of factors are supposed to take part in PD pathogenesis including alpha-synuclein aggregation, oxidative stress, mitochondrial dysfunction and apoptosis, although the precise molecular mechanism of neudegeneration remains unknown. PD is generally a sporadic neuro- logical disorder, however, rare monogenic forms have been described during previous 15 years. Despite of the fact that mutations in the leucine-rich repeat kinase (LRRK2) gene are the most common cause of inherited forms of PD known today, the mechanisms by which mutations in the LRRK2 gene lead to disease remain unclear. It's difficult to understand the signaling pathways, regulated by LRRK2 in the absence of its clear physiological substrates. The G2019S substitution was shown to be the most common in mutations' spectrum of the LRRK2 gene in different populations which makes it easier to reveal patients with LRRK2-associated PD. In this review LRRK2 influence on protein aggregation, cytoskeletal dynamics, apoptosis rate and inflammatory response is discussed. Groups of patients with inherited forms of PD with known etiology are worth to be included into investigations. It could promote our un- derstanding of the mechanisms of neurodegeneration in more common sporadic cases.
Assuntos
Apoptose/genética , Mutação de Sentido Incorreto , Doença de Parkinson , Agregação Patológica de Proteínas , Proteínas Serina-Treonina Quinases , Transdução de Sinais/genética , Substituição de Aminoácidos , Animais , Citoesqueleto/genética , Citoesqueleto/metabolismo , Citoesqueleto/patologia , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Parte Compacta da Substância Negra/metabolismo , Parte Compacta da Substância Negra/patologia , Agregação Patológica de Proteínas/genética , Agregação Patológica de Proteínas/metabolismo , Agregação Patológica de Proteínas/patologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismoRESUMO
Mutations in the Leucine Reach Repeat Kinase 2 (LRRK2) gene are the most frequent cause of familial Parkinson's disease (PD). Although the precise physiological and pathological role of LRRK2 is unclear, a direct link between mutant LRRK2 and apoptosis has been suggested. Using flow cytometric analysis (PI+Annexin V(FITC)) we showed increased spontaneous apoptosis of peripheral blood lymphocytes in patients with LRRK.2-associated PD compared to controls after 24 (P < 0.016) and 48 (P < 0.031 ) h of incubation (5 % CO2, 37 degrees C). We found the increased FAS mRNA level in peripheral blood lymphocytes of patients with LRRK2-associated PD compared to controls (P < 0.05) and to sporadic PD (sPD) (P < 0.002). Significant difference in FAS expression between patients with LRRK2-associated PD and controls remained after three years and was detected after 1 and 24 h during lymphocyte incubation (P < 0.03 and 0.05, respectively). Increased spontaneous lymphocytes apoptosis along to increased FAS expression in patients with LRRK2-associated PD suggest that LRRK2 mutations may lead to the activation of extrinsic apoptotic way.
Assuntos
Apoptose/genética , Linfócitos/patologia , Doença de Parkinson , Proteínas Serina-Treonina Quinases/genética , Idoso , Estudos de Casos e Controles , Análise Mutacional de DNA , Feminino , Citometria de Fluxo , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , Doença de Parkinson/genética , Doença de Parkinson/patologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Reação em Cadeia da Polimerase em Tempo Real , Federação Russa , Receptor fas/genéticaRESUMO
Mutations in the Leucine Reach Repeat Kinase 2 (LRRK2) gene are the most frequent cause of familial Parkinson's disease (PD). Previously, we have sequenced the coding region of the LRRK2 gene in 85 PD patients and showed the prevalence of G2019S-associated PD (G2019S-PD) among all cases of LRRK2-associated PD in Russia. Screening of the most frequent LRRK2 mutations (G2019S, R1441C, R1441G) in the extended sample of PD patients (100 familial cases, 14 relatives and 230 sporadic cases) revealed two novel families with G2019S-PD in the addition to LRRK2-associated PD cases identified earlier. In summary, the frequency of LRRK2-associated PD among familial PD cases was estimated as 8%. The G2019S mutation was the most frequent (7% - in familial and 0.5% - in sporadic PD). Comparative analyses of the age-at-onset and main neurological symptoms in 13 patients with LRRK2-associated PD (8 with G2019S, 2 - V1613A and 1 - R1441C) and 80 PD patients without mutations in the LRRK2 gene did not reveal any differences. However, the G2019S LRRK2 mutation carriers had the increased rate of drug induced side-effects in comparison with genetically undefined patients (OR=6.4, p<0.02). The data obtained could improve our understanding of the pathogenesis of LRRK2-associated PD and be useful in clinical practice during disease therapy.