한빛사논문
- 조회1,037
Won‐Seok Lee1,2,3, Laura Lavery2,3, Maxime W C Rousseaux2,3,†, Eric B Rutledge3,4, Youjin Jang2,3, Ying‐Wooi Wan2,3, Sih‐Rong Wu3,5, Wonho Kim3,6, Ismael Al‐Ramahi2,3, Smruti Rath2,3, Carolyn J Adamski2,3,6, Vitaliy V Bondar2,3, Ambika Tewari2,3, Shirin Soleimani2,3, Samantha Mota2,3, Hari K Yalamanchili3,4, Harry T Orr7, Zhandong Liu3,4, Juan Botas2,3 and Huda Y Zoghbi*,2,3,4,6
1Integrative Molecular and Biomedical Science Program, Baylor College of Medicine, Houston, TX, USA
2Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
3Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA
4Department of Pediatrics‐Neurology, Baylor College of Medicine, Houston, TX, USA
5Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA
6Howard Hughes Medical Institute, Houston, TX, USA
7Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN, USA
†Present address: Department of Cellular and Molecular Medicine, University of Ottawa Brain and Mind Research Institute, University of Ottawa, Ottawa, ON, Canada
*Corresponding author.
Abstract
A critical question in neurodegeneration is why the accumulation of disease‐driving proteins causes selective neuronal loss despite their brain‐wide expression. In Spinocerebellar ataxia type 1 (SCA1), accumulation of polyglutamine‐expanded Ataxin‐1 (ATXN1) causes selective degeneration of cerebellar and brainstem neurons. Previous studies revealed that inhibiting Msk1 reduces phosphorylation of ATXN1 at S776 as well as its levels leading to improved cerebellar function. However, there are no regulators that modulate ATXN1 in the brainstem—the brain region whose pathology is most closely linked to premature death. To identify new regulators of ATXN1, we performed genetic screens and identified a transcription factor‐kinase axis (ZBTB7B‐RSK3) that regulates ATXN1 levels. Unlike MSK1, RSK3 is highly expressed in the human and mouse brainstems where it regulates Atxn1 by phosphorylating S776. Reducing Rsk3 rescues brainstem‐associated pathologies and deficits, and lowering Rsk3 and Msk1 together improves cerebellar and brainstem function in an SCA1 mouse model. Our results demonstrate that selective vulnerability of brain regions in SCA1 is governed by region‐specific regulators of ATXN1, and targeting multiple regulators could rescue multiple degenerating brain areas.
논문정보
- Research article
- 2021년 03월 (BRIC 등록일 2021-03-25)
- 국외 연구진
- 의약학 > 분자세포의학
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