title: T1-11 and JMF1907 ameliorate polyglutamine-expanded ataxin-3-induced neurodegeneration, transcriptional dysregulation and ataxic symptom in the SCA3 transgenic mouse.
abstract: 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.
authors.affiliation: Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC.
authors.forename: An-Hsun
authors.initials: AH
authors.lastname: Chou
authors.affiliation: Chang Gung University of Science and Technology, Taoyuan, Taiwan, ROC.
authors.forename: Ying-Ling
authors.initials: YL
authors.lastname: Chen
authors.affiliation: Neuroscience Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC.
authors.forename: Ching-Chi
authors.initials: CC
authors.lastname: Chiu
authors.affiliation: Department of Physiology and Pharmacology, College of Medicine, Chang Gung University, Taoyuan, Taiwan, ROC.
authors.forename: Shin-Je
authors.initials: SJ
authors.lastname: Yuan
authors.affiliation: Neuroscience Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC; Department of Neurology, Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC; College of Medicine, Chang Gung University, Taoyuan, Taiwan, ROC.
authors.forename: Yi-Hsin
authors.initials: YH
authors.lastname: Weng
authors.affiliation: Neuroscience Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC; Department of Neurology, Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC; College of Medicine, Chang Gung University, Taoyuan, Taiwan, ROC.
authors.forename: Tu-Hsueh
authors.initials: TH
authors.lastname: Yeh
authors.affiliation: National Research Institute of Chinese Medicine, Taipei, Taiwan, ROC.
authors.forename: Yun-Lian
authors.initials: YL
authors.lastname: Lin
authors.affiliation: Department of Chemistry, National Taiwan University, Taipei, Taiwan, ROC.
authors.forename: Jim-Min
authors.initials: JM
authors.lastname: Fang
authors.affiliation: Neuroscience Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC; Department of Physiology and Pharmacology, College of Medicine, Chang Gung University, Taoyuan, Taiwan, ROC; Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan, ROC. Electronic address: hlwns@mail.cgu.edu.tw.
authors.forename: Hung-Li
authors.initials: HL
authors.lastname: Wang
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D000067699:Ataxin-3 / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D017827:Machado-Joseph Disease / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011149:Pons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: C494827:Bax protein, mouse; C494812:Bcl2l1 protein, mouse; D007211:Indoles; C000610187:N6-(3-indolylethyl)adenosine; C000610186:N6-(4-hydroxybenzyl)adenosine; D018696:Neuroprotective Agents; D012097:Repressor Proteins; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; C092341:ATXN3 protein, human; D000067699:Ataxin-3; C505409:Casp3 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053453:Caspase 9; D046988:Proteasome Endopeptidase Complex; D000241:Adenosine
keywords: Cerebellum; JMF1907; Polyglutamine-expanded ataxin-3; Pontine nuclei; SCA3; SCA3 transgenic mice; T1-11