**1. Introduction**

Parkinson's disease (PD) is a common disease whose prevalence is increasing owing to the aging society. PD is clinically characterized by movement disabilities, such as resting tremor, rigidity, and bradykinesia [1]. PD is also defined pathologically by the selective degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and by the cytoplasmic accumulation of proteinaceous inclusions, termed Lewy bodies [2,3]. Dopa-responsive dystonia (DRD), also 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]. As widely known, PD and DRD are neurodegenerative disorders that predominately affect midbrain dopamine-producing neurons. Though dysfunctions of the dopaminergic system are involved in neurological disorders, such as Tourette's syndrome [7], schizophrenia [8,9], pituitary tumors [10], PD [11–15], and DRD [4,5,16], the loss of nigrostriatal tyrosine hydroxylase (TH) protein is distinctive in PD and DRD. The etiology of PD and DRD has been studied in the past quarter-century; however, the molecular mechanism of the onset of the disorders has not been completely elucidated. In particular, 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. In this review, 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. We also 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.

### **2. Pathology of Parkinson's Disease and Dopa-Responsive Dystonia**

PD was first diagnosed and described in detail by James Parkinson in 1817 [1]. PD a ffects over 10 million worldwide, particularly 1%–3% of the global population aged over 60 years and up to 50% of individuals aged over 85 [17]. The clinical features of PD are resting tremor, rigidity, bradykinesia, gait disturbances, postural instability [1], and dementia, which becomes common in the advanced stage of the disease [18]. Pathologically, PD is characterized by the loss of dopamine-biosynthesizing neurons in the substantia nigra pars compacta (SNpc), and by the abnormal deposition of α-synuclein in the cell body (called Lewy body) and in neuronal processes (called Lewy neurites). The risk of developing PD is twice as high in men than in women; particularly, women have a higher mortality rate and faster progression of the disease [19]. Moreover, 90% of PD are sporadic, and hereditary and environmental factors are thought to be involved in the etiology of PD. Currently, over 20 causative or putative genes of hereditary PD have been identified by genetic linkage analysis [20]; for example, *SNCA* (*PARK1*, *PARK4*), *Parkin* (*PARK2*), *DJ-1* (*PARK7*), and *LRRK2* (*PARK8*) [21–27], which encode α-synuclein, Parkin, protein/nucleic acid deglycase DJ-1, and leucine-rich repeat kinase 2 (LRRK2) protein, respectively. These di fferent gene mutations in familial PD point to the possibility that an alteration in protein conformation and/or degradation could be a key to the degenerative process.

Another dopaminergic disorder, dystonia, is a heterogenous, neurological disorder characterized by abnormal involuntary sustained muscle contractions, frequently causing twisting and repetitive movements or abnormal postures [28]. It is believed that approximately 70% of all patients with dystonia have idiopathic rather than symptomatic dystonia. The mechanisms of dystonia pathogenesis include abnormalities in the regulation of dopaminergic transcription, nigrostriatal dopamine signaling, and loss of inhibition at neuronal circuits. There are at least 11 di fferent genes involved in autosomal dominant inherited dystonia, one in autosomal recessive inherited dystonia, and another in X-linked recessive inherited dystonia [29]. One of the most common genetic dystonia, dopa-responsive dystonia (DRD, *DYT5*), is mainly caused by the mutation of *GCH1* [4,30], which encodes GTP cyclohydrolase 1 (GCH1). Women are more commonly a ffected, with men showing a lower penetrance of mutations [31,32]; this disease develops in early childhood at approximately age 5–8 [4].

In common, PD and DRD are associated with impaired nigrostriatal dopaminergic function [33]. Nigrostriatal dopaminergic projections play a central role in the control of voluntary movements, and their degeneration has been implicated in Parkinsonian clinical symptoms. In addition, the dopaminergic system, originating in the SNpc and the ventral tegmental area (VTA), which mainly projects to the striatum (mesostriatal pathway) and the prefrontal context (mesocortical pathway), plays a major motivational role in behavioral actions [34–36]. Consistently, lesions in nigral neurons lead to simultaneous dysfunction of agonist and antagonist muscle pairs in animal models of parkinsonism [37] and idiopathic PD [15]. The dopaminergic function is regulated by dopamine, which is biosynthesized from L-tyrosine by TH and aromatic L-amino acid decarboxylase (AADC). TH requires tetrahydrobiopterin, which is biosynthesized by GCH1, to perform its enzymatic activity. Because the enzymatic activity of TH protein strictly controls the rate-limiting step of dopamine biosynthesis, unlike those of other dopamine biosynthesizing enzymes, the expression level and activity of TH directly a ffect intracellular dopamine amount. Thus, we next focus on the physiological features of TH protein and its implications in PD and DRD pathogenesis.
