Synaptic Zinc: An Emerging Player in Parkinson’s Disease

Alterations of zinc homeostasis have long been implicated in Parkinson’s disease (PD). Zinc plays a complex role as both deficiency and excess of intracellular zinc levels have been incriminated in the pathophysiology of the disease. Besides its role in multiple cellular functions, Zn(2+) also acts as a synaptic transmitter in the brain. In the forebrain, subset of glutamatergic neurons, namely cortical neurons projecting to the striatum, use Zn(2+) as a messenger alongside glutamate. Overactivation of the cortico-striatal glutamatergic system is a key feature contributing to the development of PD symptoms and dopaminergic neurotoxicity. Here, we will cover recent evidence implicating synaptic Zn(2+) in the pathophysiology of PD and discuss its potential mechanisms of actions. Emphasis will be placed on the functional interaction between Zn(2+) and glutamatergic NMDA receptors, the most extensively studied synaptic target of Zn(2+).