H1152 promotes the degradation of polyglutamine-expanded ataxin-3 or ataxin-7 independently of its ROCK-inhibiting effect and ameliorates mutant ataxin-3-induced neurodegeneration in the SCA3 transgenic mouse.
Spinocerebellar ataxia type 3 (SCA3) caused by polyglutamine-expanded ataxin-3 is the most prevalent subtype of spinocerebellar ataxias. A compound, which decreases protein level of mutant ataxin-3 in SCA3 affected CNS regions, should be a promising therapeutic agent for SCA3. SCA3 and Huntington's disease (HD) belong to a family of polyglutamine neurodegenerative diseases. Rho-kinase (ROCK) inhibitor Y27632 reduced brain level of polyglutamine-expanded huntingtin in HD transgenic mouse. Therefore, we tested the possibility that ROCK inhibitors, Y27632, H1152 and GSK429286, downregulate protein expression of polyglutamine-expanded ataxin-3-Q79. Y27632 or H1152 reduced protein level of HA-tagged ataxin-3-Q79 (ATX-3-Q79HA) expressed in HEK 293 cells. Compared to Y27632, H1152 decreased ATX-3-Q79HA protein level with a significantly more potency and efficacy. H1152 also reduced protein level of HA-tagged polyglutamine-expanded ataxin-7-Q52 (ATX-7-Q52HA), which causes spinocerebellar ataxia type 7 (SCA7). H1152 decreased ATX-3-Q79HA or ATX-7-Q52HA protein level in vitro by augmenting proteasome activity and promoting ATX-3-Q79HA or ATX-7-Q52HA degradation. GSK429286, which is structurally different from H1152 but equally inhibits ROCK, failed to affect protein level of ATX-3-Q79HA or ATX-7-Q52HA. Furthermore, shRNA-mediated suppression of ROCK1 or ROCK2 expression in 293 cells did not affect protein level of ATX-3-Q79HA or ATX-7-Q52HA and H1152 reduction of ATX-3-Q79HA. Daily intraperitoneal administration of H1152 significantly decreased protein level of ATX-3-Q79HA in the cerebellum, pontine nuclei and spinal cord of SCA3 transgenic mice. H1152 also ameliorated pontine neuronal death and neurological phenotype of SCA3 transgenic mice. Our results suggest that H1152 might be an effective therapeutic agent for SCA3 or SCA7.
Department of Physiology and Pharmacology, Chang Gung University School of Medicine, 259 Wen-Hwa 1 Road, Kwei-San, Tao-Yuan, Taiwan, ROC. hlwns@mail.cgu.edu.tw
Hung-Li
HL
Wang
Su-Huei
SH
Hu
An-Hsun
AH
Chou
Shang-Seng
SS
Wang
Yi-Hsin
YH
Weng
Tu-Hsueh
TH
Yeh
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000577:Amides / Q000494:pharmacology; D000818:Animals; D000067699:Ataxin-3; D000067719:Ataxin-7; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007191:Indazoles / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009410:Nerve Degeneration / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D009687:Nuclear Proteins / Q000009:adverse effects / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D014157:Transcription Factors / Q000009:adverse effects / Q000235:genetics / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
C459092:2-methyl-1-((4-methyl-5-isoquinolinyl)sulfonyl)homopiperazine; C584554:4-(4-(trifluoromethyl)phenyl)-N-(6-fluoro-1H-indazol-5-yl)-2-methyl-6-oxo-1,4,5,6-tetrahydro-3-pyridinecarboxamide; C000593829:ATXN7 protein, human; D000577:Amides; D000067719:Ataxin-7; C000593831:Atxn7 protein, mouse; D007191:Indazoles; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009687:Nuclear Proteins; D010455:Peptides; D011725:Pyridines; D014157:Transcription Factors; C108830:Y 27632; D009536:Niacinamide; C097188:polyglutamine; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; D000067699:Ataxin-3; C511594:Atxn3 protein, mouse; D046988:Proteasome Endopeptidase Complex