Although PD is traditionally viewed as a motor disorder
Although PD is traditionally viewed as a motor disorder, evidence from numerous epidemiologic (Shiba et al., 2000) as well as case–control studies (Richard, 2005) suggest the occurrence of non-motor symptoms including hyposmia/anosmia, gastrointestinal disturbances, sleep abnormalities, autonomic dysfunction, anxiety, depression, and impaired cognition at premotor stages of PD (Braak et al., 2003, Langston, 2006). Among these, anxiety disorders frequently occur in association with PD (up to 40% of PD patients) and may be important causes of morbidity (Richard, 2005). While the pathophysiology of anxiety and depressive symptoms in PD patients is largely uncertain, loss of DArgic neurons in the nigrostriatal pathway is unlikely to be the cause. Such symptoms may instead be linked to other specific neurobiological processes that occur in PD. The norepinephrinergic (NErgic) system in the A 61603 hydrobromide of plays an important role in attention, sleep/wakefulness, learning and memory, emotion, and central responses to stress (Sara, 2009). The central NErgic system has also been implicated in anxiety states and depression (Charney, 2003). Norepinephrine (NE) is synthesized by sequential enzymatic reaction of tyrosine. Dopamine β-hydroxylase (DBH) converts DA to NE, which is a hallmark protein of NErgic cells and is specifically expressed in NErgic neurons and chromaffin cells of the adrenal medulla. In the brain, NErgic neuronal activity originates from the locus coeruleus (LC) and is increased under stressful conditions by upregulation of enzymatic activity and transcription of tyrosine hydroxylase (TH) and DBH (Sabban and Kvetnanský, 2001, Sabban and Serova, 2007, Wong and Tank, 2007). Regulation of DBH activity occurs at the transcriptional level; multiple intracellular effectors such as cyclic AMP (cAMP), glucocorticoids, calcium and related signaling molecules, and nerve growth factor are involved in its transcriptional regulation (Acheson et al., 1984, Kim et al., 1993, Kim et al., 1994, Kobayashi et al., 1989, McMahon and Sabban, 1992, Otten and Thoenen, 1976, Sabban et al., 1983). cAMP response element (CRE) is an essential positive element for both basal and stress response-inducible transcriptional regulations of the gene encoding DBH (Ishiguro et al., 1993, Lamouroux et al., 1993); therefore, interference with CRE-mediated DBH regulation may be involved in the etiology of anxious/depressive symptoms in PD (Lamouroux et al., 1993, Lieberman, 2006). Several independent investigators have documented disturbances in central NErgic systems and early involvement of the LC in PD (Dickson et al., 2009, German et al., 1992, Marien et al., 2004, Schapira et al., 2006). Experimental lesions of the LC have also been shown to exacerbate PD pathology and behavioral symptoms in animal models (Marien et al., 1993, Mavridis et al., 1991, Srinivasan and Schmidt, 2003). Postmortem examinations indicate that the level of NE in the LC is reduced in PD, which is associated with a loss of pigmented neurons and the formation of Lewy body inclusions (Forno et al., 1993). Taken together, these results suggest that NE dysfunction occurs prior to significant loss of DArgic neurons and may be responsible for both motor and non-motor symptoms in PD patients. The small (~14kDa) acidic protein alpha-synuclein (α-SYN) is a major component of Lewy bodies and is suggested to be a genetic risk factor for PD. The A53T, A30P, and E46K mutations in the gene encoding α-SYN are associated with an autosomal dominant familial type of PD (Giasson et al., 2002, Krüger et al., 1998, Lee et al., 2002, Polymeropoulos et al., 1997, van der Putten et al., 2000, Zarranz et al., 2004). α-SYN is expressed predominantly in presynaptic terminals and plays a role in synaptic vesicle recycling, storage, and release of neurotransmitters for normal neurotransmission (Abeliovich et al., 2000, Yavich et al., 2004, Yavich et al., 2006). Both missense and multiplication mutations of α-SYN affect DA transmission by interfering with the synthesis and vesicular storage of DA (Lotharius and Brundin, 2002). α-SYN interacts with TH and reduces TH activity, phosphorylation (Perez et al., 2002), and expression (Yu et al., 2004). More interestingly, our previous study revealed that overexpression of wild-type or mutant α-SYN interferes with CRE-mediated transcriptional regulation of TH (Kim et al., 2011). In addition, very recent evidence suggested that impairments in autonomic modulation of cardiac function were shown in mice overexpressing α-SYN (Fleming et al., 2013), which is also frequently observed in the synucleinopathy PD. Because significantly increased expression of α-SYN is observed in the brains of PD patients and aged populations (DeMarch et al., 2007), it is interesting to consider that elevation of α-SYN, especially its mutant form, caused by a specific disease or the normal aging process could be associated with mood changes by dysregulating NE neurotransmission.