Journal
NATURE COMMUNICATIONS
Volume 7, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms10332
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Funding
- Michael J. FOX foundation
- US National Institutes of Health [RO1HL71793]
- Institut de Recherche Servier
- Department of Medicine at Boston University School of Medicine
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL071793] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES [R01ES020395] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS060872, R01NS089544] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R01AG050471] Funding Source: NIH RePORTER
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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 Ca2+ signalling pathway. Analysis of the cells from idPD patients reveals a significant deficiency in store-operated PLA2g6-dependent Ca2+ signalling, which we can mimic in a novel B6.Cg-Pla2g6(Delta Ex2-VB) (PLA2g6 ex2(KO)) mouse model. Here we demonstrate that genetic or molecular impairment of PLA2g6-dependent Ca2+ 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.
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