Redox Sensitivity of Tyrosine Hydroxylase Activity and Expression in Dopaminergic Dysfunction

Abstract

Oxidant molecules generated during neuronal metabolism appear to play a significant role in the processes of aging and neurodegeneration. Increasing experimental evidence suggests the noteworthy relevance of the intracellular reduction-oxidation (redox) balance for the dopaminergic (DA-ergic) neurons of the substantia nigra pars compacta. These cells possess a distinct physiology intrinsically associated with elevated reactive oxygen species production, conferring on them a high vulnerability to free radical damage, one of the major causes of selective DA-ergic neuron dysfunction and degeneration related to neurological disorders such as Parkinson's disease. Tyrosine hydroxylase (tyrosine 3-monooxygenase; E.C. 1.14.16.2; TH) activity represents the rate-limiting biochemical event in DA synthesis. TH activity, metabolism and expression are finely tuned by several regulatory systems in order to maintain a crucial physiological condition in which DA synthesis is closely coupled to its secretion. Alterations of these regulatory systems of TH functions have indeed been thought to be key events in the DA-ergic degeneration. TH has seven cysteine residues presenting thiols. Depending on the oxido-reductive (redox) status of the cellular environment, thiols exist either in the reduced form of free thiols or oxidized to disulfides. The formation of disulfides in proteins exerts critical regulatory functions both in physiological and in pathological conditions when oxidative stress is sustained. Several reports have recently shown that redox state changes of thiol residues, as consequence of an oxidative injury, can directly or indirectly affect the TH activity, metabolism and expression.The major focus of this review, therefore, is to report recent evidence on the redox modulation of TH activity and expression, and to provide an overview of a cellular phenomenon that might represent a target for new therapeutic strategies against the DA-ergic neurodegenerative disorders.

Alternative microglial activation is associated with cessation of progressive dopamine neuron loss in mice systemically administered lipopolysaccharide

“…A potential explanation for this phenomenon is that microglial cells, although ubiquitously present in the brain, are more densely populated in the hippocampus, olfactory telencephalon, basal ganglia, and substantia nigra compared to other regions (Lawson et al, 1990; Mittelbronn et al, 2001). Similarly, dopamine neurons of the SNpc are postulated to be more susceptible to inflammatory insult, most likely as a consequence of the increased presence of inflammatory cells and increased reactive oxygen species (Di Giovanni et al, 2012; Perry et al, 2007). …”

Tyrosine hydroxylase phosphorylation in vivo

“…TH activity is controlled by multiple mechanisms, is critical for normal physiology and is implicated in certain neuropathological conditions. A number of reviews on TH have been published (Kumer & Vrana 1996;Fitzpatrick 1999;Flatmark 2000;Pardridge 2005;Benavides-Piccione & DeFelipe 2007;Nakashima et al 2009;Sumi-Ichinose et al 2010;Lenartowski & Goc 2011;Bademci et al 2012;Di Giovanni et al 2012;Khan et al 2012;Tabrez et al 2012;White & Thomas 2012;Nagatsu et al 2018).…”

Cysteines as Redox Molecular Switches and Targets of Disease

“…Recent studies describe interesting interplays between parkin oxidative modifications, its role in mitochondrial quality control and PD onset (Zhang et al, 2016). In dopaminergic neurodegenerative disorders, a key pathogenetic event is also the inactivation of tyrosine hydroxylase, a rate-limiting enzyme in dopamine and norepinephrine biosynthesis, by oxidative injury (Di Giovanni et al, 2012). …”