**Ichiro Kawahata \* and Kohji Fukunaga \***

Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan

**\*** Correspondence: kawahata@tohoku.ac.jp (I.K.); kfukunaga@tohoku.ac.jp (K.F.); Tel.: +81-22-795-6838 (I.K.); +81-22-795-6836 (K.F.); Fax: +81-22-795-6835 (I.K. & K.F.)

Received: 7 April 2020; Accepted: 25 May 2020; Published: 27 May 2020

**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.

**Keywords:** Parkinson's disease; dopa-responsive dystonia; tyrosine hydroxylase; α-synuclein; fatty acid-binding protein 3; ubiquitination; proteasomal degradation; ubiquitin-proteasome system
