LAUSR

Parkinson’s disease (PD) is recognized as the second most common neurodegenerative disorder after Alzheimer disease. Although a fascinating 200-year journey of research has revealed the multifaceted nature of PD [1, 2], its fundamental features are the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and depletion of dopamine (DA) in the striatum. Iron accumulates in normal brains with aging. Such deposition has been reported to be exacerbated in acquired neurodegenerative disorders and in genetic neurological disorders such as neurodegeneration with brain iron accumulation and Friedreich ataxia [3]. Especially in PD, potential mechanisms have been offered to explain why iron metabolism is disturbed, as well as how elevated iron leads to dopaminergic neuronal degeneration [4]. However, it has been noted that this degeneration occurs in the SNpc, while other iron-rich areas remain unaffected. Meanwhile, dopaminergic neurons survive in the adjacent ventral tegmental area, where the iron levels are lower than in the SNpc. This emphasizes the close relationship between iron and DA, two key chemical components, and thus a toxic couple in the degeneration of dopaminergic neurons [5]. The revealed aspects of iron-DA coupling are largely derived from their pro-oxidant properties. As the central neurotransmitter involved in PD, DA is synthesized by tyrosine hydroxylase in dopaminergic neurons and then stored in synaptic vesicles ready for neurotransmission. The released DA is recycled into the cytoplasm by the DA transporter. DA easily forms toxic metabolites and these processes occur predominantly in the cytoplasm. Physiologically, H2O2 is produced by a DA enzymatic process via monoamine oxidase that converts DA to 3,4-dihydroxyphenylacetic acid and then homovanillic acid. Meanwhile, oxidative circumstances facilitate DA auto-oxidation and then the non-enzymatic catalytic production of o-quinones and quinones. Apart from the processes of biosynthesis and biodegradation, the free cytoplasmic DA is tightly restricted to a minimum by the modulation of trafficking from the presynaptic terminals via the DA transporter and synaptic vesicles via vestibular monoamine transporter 2. Accumulation of a high level of free cytoplasmic DA thus triggers DA-derived cytotoxicity. Although DA is depleted in the pathological progression of PD, it has to be noted that the cytotoxicity of free DA plays a part in the vulnerability of dopaminergic neurons. Excess iron induces oxidative stress via the formation of hydroxyl radicals, leading to the peroxidation of DNA, proteins, and lipids. Recently, ferroptosis has been introduced and highlighted for triggering non-apoptotic cell death dependent on iron and reactive oxygen species. The induction of ferroptosis further leads to ferritinophagy (degradation of ferritin), which releases iron and in turn increases the labile cytoplasmic iron pool. This emphasizes the pro-oxidant nature of iron [6]. The elevated cytoplasmic iron elicits a hazardously pro-oxidant environment, although there are still arguments about whether this elevated iron is the primary insult or secondarily released from the degenerating neurons in PD. Iron becomes toxic in dopaminergic neurons by (1) reacting with H2O2 & Junxia Xie [email protected]; [email protected]