Multifunctional Metallothioneins as a Target for Neuroprotection in Parkinson’s Disease

Abstract

Parkinson’s disease (PD) is characterized by motor symptoms based on a loss of nigrostriatal dopaminergic neurons and by non-motor symptoms which precede motor symptoms. Neurodegeneration accompanied by an accumulation of α-synuclein is thought to propagate from the enteric nervous system to the central nervous system. The pathogenesis in sporadic PD remains unknown. However, many reports indicate various etiological factors, such as oxidative stress, inflammation, α-synuclein toxicity and mitochondrial impairment, drive neurodegeneration. Exposure to heavy metals contributes to these etiopathogenesis and increases the risk of developing PD. Metallothioneins (MTs) are cysteine-rich metal-binding proteins; MTs chelate metals and inhibit metal-induced oxidative stress, inflammation and mitochondrial dysfunction. In addition, MTs possess antioxidative properties by scavenging free radicals and exert anti-inflammatory effects by suppression of microglial activation. Furthermore, MTs recently received attention as a potential target for attenuating metal-induced α-synuclein aggregation. In this article, we summarize MTs expression in the central and enteric nervous system, and review protective functions of MTs against etiopathogenesis in PD. We also discuss neuroprotective strategies for the prevention of central dopaminergic and enteric neurodegeneration by targeting MTs. This review highlights multifunctional MTs as a target for the development of disease-modifying drugs for PD.

Multi-tissue transcriptomic and serum metabolomic assessment reveals systemic implications of acute ozone-induced stress response in male Wistar Kyoto rats

“…Functional differences between organ systems, potentially stemming from differences in adrenergic and glucocorticoid receptor distribution or activation, are causing tissue-speci c responses to the ozone stressor (Kalinyak et al, 1987;Paik et al, 2020). The few genes commonly changed by ozone in all tissues include several responsible for responding to cell stress, including Cdkn1a, involved in DNA damage response and cell cycle progression (Dutto et al, 2015), Gpatch4, important in nucleosome response to stress (Hirawake-Mogi et al, 2021), Mt1m and Mt2a, responders to metal and non-metal stress (Miyazaki & Asanuma, 2023), and Pcdh12, critical in cell adhesion (Rampon et al, 2005). Because ozone itself is unlikely to translocate beyond the lung upon inhalation, the conserved response across diverse organ systems is likely due to a systemic stress response.…”

Metallothionein expression in the central nervous system in response to chronic heavy metal exposure: possible neuroprotective mechanism

“…At the level of the nervous system, these proteins are present in glial cells and neurons and appear to have a protective effect against the neurotoxicity of some heavy metals such as lead, mercury and cadmium. It has been suggested that metallothioneins may be a way to prevent or treat neurodegenerative diseases (Juárez-Rebollar et al, 2017 ; Manso et al, 2011 ; Miyazaki & Asanuma, 2023 ; Samuel et al, 2021 ). In relation to this, MT2A is considered a key player in the maintenance of immune homeostasis (Jakovac et al, 2013 ) and its involvement as a neuroprotective factor has been described in different neurodegenerative diseases such as Parkinson's disease (Miyazaki et al, 2013 ), Alzheimer's disease (Chung et al, 2010 ), or amyotrophic lateral sclerosis (Brandebura et al, 2023 ).…”

Harnessing Ferroptosis to Overcome Drug Resistance in Colorectal Cancer: Promising Therapeutic Approaches

“…Furthermore, MTs' interaction with ferritin, a protein involved in iron storage, is suggested to have a potential impact on iron release under oxidative conditions. In the context of Parkinson's disease (PD), where iron accumulation is linked to ferroptosis and disease pathogenesis, understanding the interplay between MTs and iron metabolism may offer insights into potential neuroprotective strategies [119].…”