Degradation of Tyrosine Hydroxylase by the Ubiquitin-Proteasome System in the Pathogenesis of Parkinson’s Disease and Dopa-Responsive Dystonia

• Main Authors: Ichiro Kawahata, Kohji Fukunaga
• Format: Article
• Language: English
• Published: MDPI AG 2020-05-01
• Series: International Journal of Molecular Sciences
• Subjects: Parkinson’s disease; dopa-responsive dystonia; tyrosine hydroxylase; α-synuclein; fatty acid-binding protein 3; ubiquitination
• Online Access: https://www.mdpi.com/1422-0067/21/11/3779

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.