Impairment of PARK14-dependent Ca(2+) signalling is a novel determinant of Parkinson's disease.
Nat Commun
; 7: 10332, 2016 Jan 12.
Article
em En
| MEDLINE
| ID: mdl-26755131
ABSTRACT
The etiology of idiopathic Parkinson's disease (idPD) remains enigmatic despite recent successes in identification of genes (PARKs) that underlie familial PD. To find new keys to this incurable neurodegenerative disorder we focused on the poorly understood PARK14 disease locus (Pla2g6 gene) and the store-operated Ca(2+) signalling pathway. Analysis of the cells from idPD patients reveals a significant deficiency in store-operated PLA2g6-dependent Ca(2+) signalling, which we can mimic in a novel B6.Cg-Pla2g6(ΔEx2-VB) (PLA2g6 ex2(KO)) mouse model. Here we demonstrate that genetic or molecular impairment of PLA2g6-dependent Ca(2+) signalling is a trigger for autophagic dysfunction, progressive loss of dopaminergic (DA) neurons in substantia nigra pars compacta and age-dependent L-DOPA-sensitive motor dysfunction. Discovery of this previously unknown sequence of pathological events, its association with idPD and our ability to mimic this pathology in a novel genetic mouse model opens new opportunities for finding a cure for this devastating neurodegenerative disease.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Doença de Parkinson
/
Encéfalo
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Sinalização do Cálcio
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Fosfolipases A2 do Grupo VI
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Neurônios Dopaminérgicos
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Movimento
Tipo de estudo:
Prognostic_studies
Limite:
Adult
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Aged
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Animals
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Humans
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Middle aged
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article