Defective Protein Identified as a Novel Determinant in Parkinson’s Disease

Margarida Azevedo, MSc avatar

by Margarida Azevedo, MSc |

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A novel determinant for Parkinson’s Disease as been discovered: a previously unknown defect in the function of the Pla2g6 protein leads to calcium homeostasis disruption and neuronal cell death. The research paper, entitled “Impairment of PARK14-dependent Ca2+ signalling is a novel determinant of Parkinson’s disease,” was published in Nature Communications.

While some Parkinson’s Disease (PD) patients have a family history of the disease, most cases are not inherited and its underlying causes remain unclear, though scientists believe they stem from a combination of genetic, environmental and epigenetic factors. According to the National Parkinson Foundation, about 10 to 15% of Parkinson’s cases are thought to derive from genetic causes, namely genetic mutations in specific genes (PARKs). Most PD cases however are idiopathic, with no clear underlying triggering mechanism.

Researchers at the Boston University School of Medicine focused on the poorly understood PARK14 disease locus (Pla2g6 gene) and Ca2+ (calcium) signaling pathway. Analysis of cells from patients with idiopathic PD (the most common form of parkinsonism, so called due to the unknown cause of the condition) revealed a previously unknown deficiency in PLA2g6-dependent Ca2+ signaling. Researchers demonstrated that the molecular impairment in the PLA2g6 protein caused deregulation of calcium balance in the cells, which in turn triggered autophagic dysfunction and progressive loss of dopaminergic (DA) neurons, ultimately leading to motor dysfunction in a novel mouse model developed by the team. The discovery of this previously unknown sequence of events sheds light on the pathogenesis of PD and could lead to the discovery of new therapeutic strategies.

Corresponding author Victoria Bolotina, PhD, professor of medicine at BUSM, commented in a press release, “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. 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.”

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