Ca²⁺ Dyshomeostasis Links Risk Factors to Neurodegeneration in Parkinson's Disease

Parkinson's disease (PD), a common neurodegenerative disease characterized by motor dysfunction, results from the death of dopaminergic neurons in the substantia nigra pars compacta (SNc). Although the precise causes of PD are still unknown, several risk factors for PD have been determined, including aging, genetic mutations, environmental factors, and gender. Currently, the molecular mechanisms underlying risk factor-related neurodegeneration in PD remain elusive. Endoplasmic reticulum stress, excessive reactive oxygen species production, and impaired autophagy have been implicated in neuronal death in the SNc in PD. Considering that these pathological processes are tightly associated with intracellular Ca²⁺, it is reasonable to hypothesize that dysregulation of Ca²⁺ handling may mediate risk factors-related PD pathogenesis. We review the recent findings on how risk factors cause Ca²⁺ dyshomeostasis and how aberrant Ca²⁺ handling triggers dopaminergic neurodegeneration in the SNc in PD, thus putting forward the possibility that manipulation of specific Ca²⁺ handling proteins and subcellular Ca²⁺ homeostasis may lead to new promising strategies for PD treatment.