Dual targeting of brain region-specific kinases potentiates neurological rescue in Spinocerebellar ataxia type 1
© 2021 The Authors..
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2021 |
|---|---|
| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:40 |
|---|---|
| Enthalten in: |
The EMBO journal - 40(2021), 7 vom: 01. Apr., Seite e106106 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Lee, Won-Seok [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 22.10.2021 Date Revised 02.04.2022 published: Print-Electronic GEO: GSE151276 Citation Status MEDLINE |
|---|
| doi: |
10.15252/embj.2020106106 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM322663334 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM322663334 | ||
| 003 | DE-627 | ||
| 005 | 20231225182521.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2021 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.15252/embj.2020106106 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1075.xml |
| 035 | |a (DE-627)NLM322663334 | ||
| 035 | |a (NLM)33709453 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Lee, Won-Seok |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Dual targeting of brain region-specific kinases potentiates neurological rescue in Spinocerebellar ataxia type 1 |
| 264 | 1 | |c 2021 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 22.10.2021 | ||
| 500 | |a Date Revised 02.04.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a GEO: GSE151276 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2021 The Authors. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 4 | |a Ataxin-1 | |
| 650 | 4 | |a MSK1 | |
| 650 | 4 | |a RSK3 | |
| 650 | 4 | |a Spinocerebellar ataxia type 1 | |
| 650 | 4 | |a selective vulnerability | |
| 650 | 7 | |a Ataxin-1 |2 NLM | |
| 650 | 7 | |a Atxn1 protein, mouse |2 NLM | |
| 650 | 7 | |a DNA-Binding Proteins |2 NLM | |
| 650 | 7 | |a Transcription Factors |2 NLM | |
| 650 | 7 | |a Zbtb7b protein, mouse |2 NLM | |
| 650 | 7 | |a Ribosomal Protein S6 Kinases, 90-kDa |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a mitogen and stress-activated protein kinase 1 |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a ribosomal protein S6 kinase, 90kDa, polypeptide 3 |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 700 | 1 | |a Lavery, Laura |e verfasserin |4 aut | |
| 700 | 1 | |a Rousseaux, Maxime W C |e verfasserin |4 aut | |
| 700 | 1 | |a Rutledge, Eric B |e verfasserin |4 aut | |
| 700 | 1 | |a Jang, Youjin |e verfasserin |4 aut | |
| 700 | 1 | |a Wan, Ying-Wooi |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Sih-Rong |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Wonho |e verfasserin |4 aut | |
| 700 | 1 | |a Al-Ramahi, Ismael |e verfasserin |4 aut | |
| 700 | 1 | |a Rath, Smruti |e verfasserin |4 aut | |
| 700 | 1 | |a Adamski, Carolyn J |e verfasserin |4 aut | |
| 700 | 1 | |a Bondar, Vitaliy V |e verfasserin |4 aut | |
| 700 | 1 | |a Tewari, Ambika |e verfasserin |4 aut | |
| 700 | 1 | |a Soleimani, Shirin |e verfasserin |4 aut | |
| 700 | 1 | |a Mota, Samantha |e verfasserin |4 aut | |
| 700 | 1 | |a Yalamanchili, Hari K |e verfasserin |4 aut | |
| 700 | 1 | |a Orr, Harry T |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Zhandong |e verfasserin |4 aut | |
| 700 | 1 | |a Botas, Juan |e verfasserin |4 aut | |
| 700 | 1 | |a Zoghbi, Huda Y |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t The EMBO journal |d 1982 |g 40(2021), 7 vom: 01. Apr., Seite e106106 |w (DE-627)NLM012617202 |x 1460-2075 |7 nnns |
| 773 | 1 | 8 | |g volume:40 |g year:2021 |g number:7 |g day:01 |g month:04 |g pages:e106106 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.15252/embj.2020106106 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 40 |j 2021 |e 7 |b 01 |c 04 |h e106106 | ||