T1-11 and JMF1907 ameliorate polyglutamine-expanded ataxin-3-induced neurodegeneration, transcriptional dysregulation and ataxic symptom in the SCA3 transgenic mouse
Journal
Neuropharmacology
Journal Volume
99
Pages
308-317
Date Issued
2015
Author(s)
Chou, A.-H.
Chen, Y.-L.
Chiu, C.-C.
Yuan, S.-J.
Weng, Y.-H.
Yeh, T.-H.
Lin, Y.-L.
Wang, H.-L.
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. ? 2015 Published by Elsevier Ltd.
Subjects
Cerebellum; JMF1907; Polyglutamine-expanded ataxin-3; Pontine nuclei; SCA3; SCA3 transgenic mice; T1-11
SDGs
Other Subjects
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
Type
journal article