https://scholars.lib.ntu.edu.tw/handle/123456789/391984
標題: | T1-11 and JMF1907 ameliorate polyglutamine-expanded ataxin-3-induced neurodegeneration, transcriptional dysregulation and ataxic symptom in the SCA3 transgenic mouse | 作者: | Chou, A.-H. Chen, Y.-L. Chiu, C.-C. Yuan, S.-J. Weng, Y.-H. Yeh, T.-H. Lin, Y.-L. Fang, J.-M. Wang, H.-L. JIM-MIN FANG |
關鍵字: | Cerebellum; JMF1907; Polyglutamine-expanded ataxin-3; Pontine nuclei; SCA3; SCA3 transgenic mice; T1-11 | 公開日期: | 2015 | 卷: | 99 | 起(迄)頁: | 308-317 | 來源出版物: | Neuropharmacology | 摘要: | More studies are required to develop therapeutic agents for treating spinocerebellar ataxia type 3 (SCA3), which is caused by mutant polyglutamine-expanded ataxin-3 and is the most prevalent subtype of spinocerebellar ataxias. T1-11 [N6-(4-Hydroxybenzyl) adenosine], isolated from a Chinese medicinal herb Gastordia elata, is an adenosine A2A receptor agonist. SCA3 and Huntington's disease (HD) belong to a family of polyglutamine neurodegenerative diseases. T1-11 exerted a therapeutic effect on HD transgenic mouse by decreasing protein level of polyglutamine-expanded huntingtin in the striatum. In the present study, we test the possibility that T1-11 or JMF1907 [N6-(3-Indolylethyl) adenosine], a synthetic analog of T1-11, alleviates pontine neuronal death, cerebellar transcriptional downregulation and ataxic symptom in the SCA3 transgenic mouse expressing HA-tagged polyglutamine-expanded ataxin-3-Q79 (ataxin-3-Q79HA). Daily oral administration of T1-11 or JMF1907 prevented neuronal death of pontine nuclei in the SCA3 mouse with a dose-dependent manner. Oral application of T1-11 or JMF1907 reversed mutant ataxin-3-Q79-induced cerebellar transcriptional repression in the SCA3 transgenic mouse. T1-11 or JMF1907 ameliorated the symptom of motor incoordination displayed by SCA3 mouse. Oral administration of T1-11 or JMF1907 significantly decreased protein level of ataxin-3-Q79HA in the pontine nuclei or cerebellum of SCA3 mouse. T1-11 or JMF1907 significantly augmented the chymotrypsin-like activity of proteasome in the pontine nuclei or cerebellum of SCA3 mouse. Our results suggests that T1-11 and JMF1907 alleviate pontine neuronal death, cerebellar transcriptional downregulation and ataxic symptom of SCA3 transgenic mouse by augmenting the proteasome activity and reducing the protein level of polyglutamine-expanded ataxin-3-Q79 in the pontine nuclei and cerebellum. ? 2015 Published by Elsevier Ltd. |
URI: | http://www.scopus.com/inward/record.url?eid=2-s2.0-84939791439&partnerID=MN8TOARS http://scholars.lib.ntu.edu.tw/handle/123456789/391984 |
DOI: | 10.1016/j.neuropharm.2015.08.009 | SDG/關鍵字: | ataxin 3; caspase 3; caspase 9; central stimulant agent; chymotrypsin; n6 (3 indolylethyl)adenosine; n6 (4 hydroxybenzyl)adenosine; polyglutamine; proteasome; unclassified drug; adenosine; ataxin 3; ATXN3 protein, human; Bax protein, mouse; Bcl2l1 protein, mouse; Casp3 protein, mouse; Casp9 protein, mouse; caspase 3; caspase 9; indole derivative; N6-(3-indolylethyl)adenosine; N6-(4-hydroxybenzyl)adenosine; neuroprotective agent; proteasome; protein Bax; protein bcl x; repressor protein; animal cell; animal experiment; animal model; animal tissue; Article; ataxia; brain level; brain region; cell death; cell protection; cerebellum; controlled study; dose response; down regulation; drug effect; drug mechanism; enzyme activity; male; molecular dynamics; mouse; nerve degeneration; neuroprotection; nonhuman; pontine nucleus; priority journal; protein determination; protein expression; protein function; analogs and derivatives; animal; drug effects; genetics; human; Machado-Joseph Disease; metabolism; motor activity; nerve cell; oral drug administration; pathology; pathophysiology; physiology; pons; transgenic mouse; Adenosine; Administration, Oral; Animals; Ataxin-3; bcl-2-Associated X Protein; bcl-X Protein; Caspase 3; Caspase 9; Cell Death; Cerebellum; Dose-Response Relationship, Drug; Down-Regulation; Humans; Indoles; Machado-Joseph Disease; Mice, Transgenic; Motor Activity; Neurons; Neuroprotective Agents; Pons; Proteasome Endopeptidase Complex; Repressor Proteins |
顯示於: | 化學系 |
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