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    • Alpha SYN has no direct effect on forskolin induced CREB

    2021-05-07

    Alpha-SYN has no direct effect on forskolin-induced CREB phosphorylation, but rather blocks the stimulation of CRE-mediated transcription in the nucleus. Previously we suggested that α-SYN can enter the nucleus and is present in both cytosolic and nuclear fractions without direct interaction between α-SYN and CREB protein in the nucleus (Kim et al., 2011). To answer how α-SYN can suppress CRE-mediated DBH transcription, we evaluated whether α-SYN binds to DBH promoter region and interferes with CREB binding to CRE region. Fig. 4 shows that α-SYN interacts with the DBH promoter encompassing the region of CRE, and interferes with CREB binding to CRE region on the DBH promoter. Because CREB is a transcription factor that also plays an important role in neuronal survival by controlling the transcription of neuroprotective genes such as brain-derived neurotrophic factor (Chalovich et al., 2006), α-SYN-induced a loss of CREB function could contribute to neuronal dysfunction and neurodegeneration, too. Although not only A53T but also wild type α-SYN attenuated CRE-mediated DBH up-regulation, entered into the nucleus, and bound to the DBH promoter encompassing the region of CRE, all those effects were more significant in Viomycin overexpressing A53T. We have not fully answered in the present study by which mechanism A53T has more significant effects on DBH regulation as compared with other α-SYN forms. But in vivo data from ours (Fig. 6) as well as other groups (Graham and Sidhu, 2010) strongly support the pathogenic significance of A53T Tg mice expressing the A53T human α-SYN exhibit hyperactivity and increased/or reduced anxiety-like behavior depend on age. But overexpression of α-SYN also caused suppression of forskolin-induced DBH upregulation in NE-producing cells (Fig. 2), therefore, one cannot eliminate the possibility that elevated levels of α-SYN due to a specific disease or the normal aging process could be associated with abnormal regulation of DBH. Nagatsu (Trocewicz et al., 1982) reported a reduction in the major metabolite of NE 3-methoxy-4-hydroxyphenylglycon and the activity of DBH in the cerebrospinal fluid of PD patients. Reduced level of NE could induce significant changes in the expression of NE receptors and transporters may prompt the development or exacerbation of anxiety (Richard et al., 1999). Furthermore, lower DA/NE transporter binding in the LC is correlated with increased incidence of anxiety and depression in PD patients (Remy et al., 2005). The effect of α-SYN and its mutation on norepinephrinergic neurons shown in this study has clinical significance both in motor and non-motor symptoms in PD; 1) MPTP fails to produce PD-like motor deficits in animals (Connor et al., 2001), but displays spontaneous dyskinesias in MPTP-treated DBH knockout mice (Rommelfanger et al., 2007); and 2) LC lesions exacerbate PD neuropathology and behavioral symptoms in animal models, suggesting the loss of LC neurons contributes to motor dysfunction in PD (Fornai et al., 1997, Marien et al., 1993, Mavridis et al., 1991). In spite of a considerable amount of clinical evidences have shown that 1) PD has been clinically characterized by motor symptoms, but its initial clinical manifestations involve non-motor symptoms such as emotional and attitudinal inflexibility; 2) NE is involved intrinsically with the stress response, and related to the generation of anxiety and depressive disorders; and 3) there is extensive loss of LC neurons as well as significant reduction in DBH in PD brain (Chan-Palay, 1991, Gesi et al., 2000), the pathogenic involvement of NErgic signaling and DBH in the symptoms of PD is not focused. In the present study, we suggest that anxiety/or depressive features commonly observed in PD patients could be related to a central NE deficiency, and α-SYN, especially mutant A53T, plays a causative role in abnormal stress response and following depression/anxiety-like behaviors by interfering with CRE-mediated transcriptional regulation of DBH. Altogether our data provide information on the pathogenic mechanism of non-motor symptom in PD and insight into the physiological function of α-SYN in NErgic neuronal cells.