Discovery may lead to better understanding of disease, early diagnosis and therapeutic development
A team of local researchers have discovered a previously unknown cellular defect in patients with idiopathic Parkinson’s disease, and identified a sequence of pathological events that can trigger or accelerate premature death of certain neurons in the brain seen in this disease.
The findings, published in the journal Nature Communications, will provide a better understanding and further research towards a possible cure of Parkinson’s disease, which is a neurodegenerative disorder that affects movement and other vital functions in nearly one million people in the United States. Despite advances in understanding the causes of familial forms of this disease, the most prevalent idiopathic form of Parkinson’s disease remains a mystery.
Boston University School of Medicine (BUSM) researchers discovered that the cells of people with idiopathic Parkinson’s disease have a previously unknown defect in the function of a specific PLA2g6 protein, causing dysfunction of calcium homeostasis that can determine whether some cells will live or die.
“Idiopathic or genetic dysfunction of calcium signaling triggers a sequence of pathological events leading to autophagic dysfunction, progressive loss of dopaminergic neurons and age-dependent impairment of vital motor functions typical for Parkinson’s disease,” explained corresponding author Victoria Bolotina, PhD, professor of medicine at BUSM.
“Discovery of this new mechanism associated with human Parkinson’s disease and our ability to mimic this pathology in a novel genetic model opens new opportunities for finding a cure for this devastating neurodegenerative disease,” she added.
Funding: This work was partially supported by research grant awards from The Michael J. Fox Foundation for Parkinson’s Research, the US National Institutes of Health, SERVIER Research Institute and the Department of Medicine at Boston University School of Medicine.
Source: Kristen Perfetuo – Boston University Medical Center
Image Source: The image is credited to the researchers/Nature Communications
Original Research: Full open access research for for “Impairment of PARK14-dependent Ca2+ signalling is a novel determinant of Parkinson’s disease” by Qingde Zhou, Allen Yen, Grzegorz Rymarczyk, Hirohide Asai, Chelsea Trengrove, Nadine Aziz, Michael T. Kirber, Gustavo Mostoslavsky, Tsuneya Ikezu, Benjamin Wolozin & Victoria M. Bolotinar in Nature Communications. Published online January 12 2016 doi:10.1038/ncomms10332
Abstract
Impairment of PARK14-dependent Ca2+ signalling is a novel determinant of Parkinson’s disease
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.
“Impairment of PARK14-dependent Ca2+ signalling is a novel determinant of Parkinson’s disease” by Qingde Zhou, Allen Yen, Grzegorz Rymarczyk, Hirohide Asai, Chelsea Trengrove, Nadine Aziz, Michael T. Kirber, Gustavo Mostoslavsky, Tsuneya Ikezu, Benjamin Wolozin & Victoria M. Bolotina in Nature Communications. Published online January 12 2016 doi:10.1038/ncomms10332