Abstract
Neurodegenerative diseases affect a significant portion of the aging population. Several lines of evidence suggest a positive association between environmental exposures, which are common and cumulative in a lifetime, and development of neurodegenerative diseases. Environmental or occupational exposure to manganese (Mn) has been implicated in neurodegeneration due to its ability to induce mitochondrial dysfunction, oxidative stress, and α-synuclein (α-Syn) aggregation. The role of the α-Syn protein vis-a-vis Mn is controversial, as it seemingly plays a duplicitous role in neuroprotection and neurodegeneration. α-Syn has low affinity for Mn, however an indirect interaction cannot be ruled out. In this review we will examine the current knowledge surrounding the interaction of α-Syn and Mn in neurodegenerative process.
Highlights
Mn reaches the brain by transport across the blood-brain barrier (BBB) via various mechanisms, including divalent metal transporter 1 (DMT1) transferrin receptor (TfR), calcium (Ca) channels, members of the organic anion transporter polypeptide (OATP), or ATP- binding cassette (ABC) superfamilies, in the case of Mn bound to citrate and diffusion
DMT1, transferrin receptor (TfR), zinc transporters (ZIP8 and ZIP14), the citrate and choline transporters, the dopamine transporter (DAT), and Ca2+ channels are responsible for Mn import to the cells in the central nervous system (CNS; Crossgrove et al, 2003; Crossgrove and Yokel, 2004, 2005; Roth, 2006)
Time frame for exposure and aggregation is a major consideration as α-Syn appears to be protective early on, often acting as a metal scavenger but later contributing to protein aggregation, neurodegeneration, and cell death
Summary
Mn may alter the accumulation of other metals, such as Cu and Fe (Fitsanakis et al, 2010; Angeli et al, 2014), which have shown high affinity for α-Syn. Alpha-Syn interacts with Cu in the μM range, with effects on its fibrillation and making it prone to metal-induced oxidation, which can lead to protein aggregation (Binolfi et al, 2006). Α-Syn influence on Mn neurotoxicity (either neuroprotection or aggravation of neurotoxicity), which will be discussed below, could be due to other actions of α-Syn and not necessarily its binding to Mn. α-Synuclein and Neuroprotection against Mn-Induced Neurotoxicity α-Syn was shown to be neuroprotective against Mn-induced neurotoxicity in a transgenic N27 dopaminergic neuronal cell line stably expressing human wild-type α-Syn at physiological levels (Harischandra et al, 2015).
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