title: Impairment of PARK14-dependent Ca(2+) signalling is a novel determinant of Parkinson's disease.
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.
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
authors.forename: Qingde
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
authors.forename: Allen
authors.initials: A
authors.lastname: Yen
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Rymarczyk
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
authors.forename: Hirohide
authors.initials: H
authors.lastname: Asai
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
authors.forename: Chelsea
authors.initials: C
authors.lastname: Trengrove
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
authors.forename: Nadine
authors.initials: N
authors.lastname: Aziz
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Kirber
authors.affiliation: Center for Regenerative Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Mostoslavsky
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
authors.forename: Tsuneya
authors.initials: T
authors.lastname: Ikezu
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Wolozin
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
authors.forename: Victoria M
authors.initials: VM
authors.lastname: Bolotina
mesh_terms: D000368:Aged; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D020013:Calcium Signaling / Q000235:genetics*; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D054522:Group VI Phospholipases A2 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D009048:Motor Skills; D009068:Movement; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000166:cytology; D055815:Young Adult
chemical_list: D054522:Group VI Phospholipases A2; C516475:PLA2G6 protein, human; C516476:Pla2g6 protein, mouse