Abstract
Nigrostriatal dopaminergic systems govern physiological functions related to locomotion, and their dysfunction leads to movement disorders, such as Parkinson’s disease and dopa-responsive dystonia (Segawa disease). Previous studies revealed that expression of the gene encoding nigrostriatal tyrosine hydroxylase (TH), a rate-limiting enzyme of dopamine biosynthesis, is reduced in Parkinson’s disease and dopa-responsive dystonia; however, the mechanism of TH depletion in these disorders remains unclear. In this article, we review the molecular mechanism underlying the neurodegeneration process in dopamine-containing neurons and focus on the novel degradation pathway of TH through the ubiquitin-proteasome system to advance our understanding of the etiology of Parkinson’s disease and dopa-responsive dystonia. We also introduce the relation of α-synuclein propagation with the loss of TH protein in Parkinson’s disease as well as anticipate therapeutic targets and early diagnosis of these diseases.
Highlights
Parkinson’s disease (PD) is a common disease whose prevalence is increasing owing to the aging society
Though dysfunctions of the dopaminergic system are involved in neurological disorders, such as Tourette’s syndrome [7], schizophrenia [8,9], pituitary tumors [10], PD [11,12,13,14,15], and Dopa-responsive dystonia (DRD) [4,5,16], the loss of nigrostriatal tyrosine hydroxylase (TH) protein is distinctive in PD and DRD
We focus on the molecular mechanism of the loss of TH protein in the neurodegeneration process in PD and DRD by introducing the degradation of phosphorylated TH protein through the ubiquitin-proteasome system
Summary
Parkinson’s disease (PD) is a common disease whose prevalence is increasing owing to the aging society. Dopa-responsive dystonia (DRD), termed as Segawa disease, is a disorder that involves involuntary muscle contractions, tremors, and other uncontrolled movements, which usually appear during childhood [4]. DRD patients present with reduced nigrostriatal dopaminergic function [5,6]. PD and DRD are neurodegenerative disorders that predominately affect midbrain dopamine-producing neurons. The reason why the TH protein, which is a rate-limiting enzyme of dopamine biosynthesis, is lost in mesencephalic dopaminergic neurons in PD and DRD, and is not entirely understood. We introduce the relation between the loss of TH protein and the propagation of α-synuclein, which is a well-known protein in PD pathology, to clarify the mechanism underlying the reduction of nigrostriatal dopamine function and the loss of TH protein in these movement disorders
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