Impairment of PARK14-dependent Ca2+ signalling is a novel determinant of Parkinson's disease

Qingde Zhou, Allen Yen, Grzegorz Rymarczyk, Hirohide Asai, Chelsea Trengrove, Nadine Aziz, Michael T. Kirber, Gustavo Mostoslavsky, Tsuneya Ikezu, Benjamin Wolozin, Victoria M. Bolotina

Research output: Contribution to journalArticlepeer-review

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 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-Pla2g6ΔEx2-VB (PLA2g6 ex2KO) 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.

Original languageEnglish (US)
Article number10332
JournalNature communications
Volume7
DOIs
StatePublished - Jan 12 2016

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Fingerprint

Dive into the research topics of 'Impairment of PARK14-dependent Ca<sup>2+</sup> signalling is a novel determinant of Parkinson's disease'. Together they form a unique fingerprint.

Cite this