Abstract
Despite much efforts in the last few decades, the mechanism of degeneration of dopamine (DA) neurons in the substantia nigra (SN) in Parkinson’s disease (PD) remains unclear. This represents a major knowledge gap in idiopathic and genetic forms of PD. Among various possible key factors postulated, iron metabolism has been widely suggested to be involved with fueling oxidative stress, a known factor in the pathogenesis of PD. However, the correlation between iron and DA neuron loss, specifically in the SN, has not been described in experimental animal models with great detail, with most studies utilizing rodents and, rarely, non-human primates. In the present study, aiming to gain further evidence of a pathological role of iron in PD, we have examined the correlation of iron with DA neuron loss in a non-human primate model of PD induced by MPTP. We report a significant iron accumulation accompanied by both DA degeneration in the SN and motor deficits in the monkey that displayed the most severe PD pathology and behavioral deficits. The other two monkeys subjected to MPTP displayed less severe PD pathologies and motor deficits, however, their SN iron levels were significantly lower than controls. These findings suggest that high iron may indicate and contribute to heightened MPP+-induced PD pathology in late or severe stages of PD, while depressed levels of iron may signal an early stage of disease. Similarly, using a cell culture preparation, we have found that high doses of ferric ammonium citrate (FAC), a factor known to enhance iron accumulation, increased MPP+-induced cell death in U251 and SH-SY5Y cells, and even in control cells. However, at low dose FAC restored or increased the viability of U251 and SH-SY5Y cells in the absence or presence of MPP+. These observations imply that high levels of iron likely contribute to or heighten MPP+ toxicity in the later stages of PD. While we report reduced iron levels in the earlier stages of MPTP induced PD, the significance of these changes remains to be determined.
Highlights
Parkinson’s disease (PD) is a well-known progressive neurodegenerative disorder that involves significant degeneration of dopamine (DA) neurons in the substantia nigra (SN) (Riederer and Wuketich, 1976; Agid, 1991)
In good agreement with the in vivo studies, we have shown that the addition of ferric ammonium citrate (FAC), a known compound promoting iron accumulation, exacerbated MPTP toxicity in cultured U251 and SH-SY5Y cells when used in high concentrations
In a monkey model of PD using MPTP, we have gathered findings that support the notion that excessive iron is likely a causal factor mediating and accelerating MPTP/MPP+ toxicity leading to DA neuron cell death
Summary
Parkinson’s disease (PD) is a well-known progressive neurodegenerative disorder that involves significant degeneration of dopamine (DA) neurons in the substantia nigra (SN) (Riederer and Wuketich, 1976; Agid, 1991). The degree of iron accumulation has been shown to be correlated to disease severity in human PD (Martin-Bastida et al, 2017; An et al, 2018) This has been corroborated in animal models where unilateral injection of iron to the SN of rats resulted in DA neuron degeneration (Ben-Shachar and Youdim, 1991), infusion of ferric chloride into the SN of rats resulted in a dose-dependent progression of parkinsonism (Sengstock et al, 1993), and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) injection into the brain led to iron accumulation in the SN of monkeys (Mochizuki et al, 1994; He et al, 2003). Related animal studies are primarily rodent-based and fail to fully replicate the human disease pathology
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