T1-11 and JMF1907 ameliorate polyglutamine-expanded ataxin-3-induced neurodegeneration, transcriptional dysregulation and ataxic symptom in the SCA3 transgenic mouse

• Published in: Neuropharmacology 2015-12, Vol.99, p.308-317
• Main Authors: Chou, An-Hsun, Chen, Ying-Ling, Chiu, Ching-Chi, Yuan, Shin-Je, Weng, Yi-Hsin, Yeh, Tu-Hsueh, Lin, Yun-Lian, Fang, Jim-Min, Wang, Hung-Li
• Format: Article
• Language: English
• Subjects: Adenosine - analogs & derivatives; Adenosine - pharmacology; Administration, Oral; Animals; Ataxin-3 - genetics; Ataxin-3 - metabolism; bcl-2-Associated X Protein - metabolism; bcl-X Protein - metabolism; Caspase 3 - metabolism; Caspase 9 - metabolism; Cell Death - drug effects; Cell Death - physiology; Cerebellum; Cerebellum - drug effects; Cerebellum - metabolism; Cerebellum - pathology; Dose-Response Relationship, Drug; Down-Regulation - drug effects; Humans; Indoles - pharmacology; JMF1907; Machado-Joseph Disease - drug therapy; Machado-Joseph Disease - pathology; Machado-Joseph Disease - physiopathology; Mice, Transgenic; Motor Activity - drug effects; Motor Activity - physiology; Neurons - drug effects; Neurons - pathology; Neuroprotective Agents - pharmacology; Polyglutamine-expanded ataxin-3; Pons - drug effects; Pons - metabolism; Pons - pathology; Pontine nuclei; Proteasome Endopeptidase Complex - metabolism; Repressor Proteins - genetics; Repressor Proteins - metabolism; SCA3; SCA3 transgenic mice; T1-11
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2015.08.009

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. •T1-11 and JMF1907 prevented pontine neuronal death of SCA3 transgenic mouse.•T-11 and JMF1907 reversed cerebellar transcriptional repression in the SCA3 mouse.•T-11 and JMF1907 ameliorated ataxic symptom displayed by SCA3 transgenic mouse.•T1-11 and JMF1907 decreased ataxin-3-Q79HA level in the PN or CB of SCA3 mouse.•T1-11 and JMF1907 augmented proteasome activity in the PN or CB of SCA3 mouse.