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.