1. Zinc Deficiency and Parkinson’s Disease

Several studies have examined whether plasma and CSF zinc levels are altered in PD patients. The reported data are, however, disparate. In some studies, circulating zinc levels were lower in PD patients ^{[1][2][3][4][5][6][7][8]}, while in others they were normal or even increased ^{[9][10][11][12][13][14][15]}. Recent meta-analysis studies, though, point to lower zinc levels in serum and plasma and CSF of PD patients compared to healthy controls ^[16][17]. Findings from epidemiological studies examining the association of dietary intake of zinc and PD are also contradictory. Higher intake of zinc was associated with reduced risk of PD in some studies ^[18], but negative findings were reported by others ^[19][20]. The association between lower levels of circulating zinc and PD has been explained by its antioxidant role since this trace element is essential for a variety of enzymes and proteins (superoxide dismutase oxidative, metallothioneins, and interleukins) involved in oxidative stress and inflammation ^[21]. In support of this view, animal studies showed that exogenous zinc can produce its beneficial effects by multiple mechanisms. In vitro, zinc inhibits 6-OHDA-induced oxidative stress ^[22] and reduces methamphetamine-induced dopaminergic neurotoxicity by the increasing expression of metallothioneins, which in turn prevent the generation of reactive oxygen species ^[23][24]. Zinc treatment also reduces 

α-synuclein (α-syn), the predominant component of Lewy bodies, induced by methamphetamine in cell culture ^[25]. Finally, zinc deficiency has been suggested to lead to dysfunction of PARK2 (E3 ligase) that possesses zinc-binding domains. PARK2 binds eight zinc ions and the removal of zinc causes a near-complete unfolding of the protein and, thereby, loss of its function ^[26]. Accordingly, supplementation with zinc has been shown to increase lifespan, as well as motor function in the parkin KO Drosophila model of PD ^[27].

2. Zinc Excess and Parkinson’s Disease

²⁺ in dopaminergic neurodegeneration associated with PD. Zinc exposure has been identified as an environmental risk factor for PD ^[28] and post-mortem studies revealed excessive zinc depositions in the substantia nigra (SN) and the striatum of patients with idiopathic PD ^{[10][29][30][31][32]}. In line with these observations, in vitro and in vivo experiments with animal models of PD showed that cytosolic accumulation labile zinc is a hallmark of degenerating dopaminergic neurons ^{[33][34][35][36][37][38][39]}. Importantly, treatments with intracellular zinc chelators prevent neurodegeneration caused by many neurotoxins (6-OHDA, MPTP, and paraquat) confirming that cytosolic Zn

²⁺ accumulation contributes to dopaminergic neuronal loss ^[40][41][42]. The mechanisms responsible for Zn

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²⁺ homeostasis. In this respect, the human PARK9 (ATP13A2), a lysosomal type 5 P-type ATPase associated with autosomal recessive early-onset PD, has been shown to act as a transporter for lysosomal sequestration of cytoplasmic zinc ^[43][44][45]. In vitro, loss of PARK9 function causes an imbalance of zinc intracellular homeostasis that in turn leads to lysosomal impairment, accumulation of α-syn, and mitochondrial dysfunction ^[43][44][45].

²⁺ can also be caused by the influx of extracellular zinc into dopaminergic neurons ^[36][37][38]. In brain slices, both 6-OHDA and paraquat have been found to rapidly increase intracellular Zn

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²⁺ pool in dopaminergic cell loss, several studies showed that systemic or intra-nigral injections of exogenous zinc can, on its own, produce dopaminergic neurotoxicity ^{[33][34][46][47][48]}. For instance, chronic injections of zinc systemically cause degeneration of the nigrostriatal dopaminergic pathway and locomotor deficits in rats like the pesticide, paraquat ^[49][50][51]. Zinc treatment causes cellular dysfunction by increasing oxidative stress through activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and depletion of glutathione (GSH), which in turn trigger the apoptotic machinery leading to neuronal loss, as seen following paraquat treatment ^[33]. The motor deficits and dopaminergic cell neurodegeneration induced by chronic zinc treatments were also shown to involve activation of microglial cells and expression of inflammatory mediators (e.g., TNF-α, IL-1β) ^[52][53].

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