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Dual targeting of brain region-specific kinases potentiates neurological rescue in Spinocerebellar ataxia type 1

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.

SUBMITTER: Dr. Won-Seok Lee

PROVIDER: S-SCDT-EMBOJ-2020-106106 | biostudies-other |

REPOSITORIES: biostudies-other

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Dual targeting of brain region-specific kinases potentiates neurological rescue in Spinocerebellar ataxia type 1.

Project description: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.

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Dual targeting of brain region-specific kinases potentiates neurological rescue in Spinocerebellar ataxia type 1

Project description:We performed an shRNA screen to identify novel ATXN1 protein level regulators in hope of finding some that may improve brainstem function in SCA1. We found that two closely related BTB-ZF transcription factors, ZBTB7A and ZBTB7B, positively regulate ATXN1 levels in vitro and in vivo, with ZBTB7B displaying a more pronounced effect. ZBTB7B regulates ATXN1 by regulating the transcription of RSK3 (RPS6KA2). RSK3 in turn regulates ATXN1 by phosphorylating its serine 776 (S776), a residue critical for ATXN1 stability, which is similar to another one previously identified ATXN1 kinase, MSK1. However, despite the convergent function of the two kinases, each kinase selectively regulates Atxn1 in a brain region-dependent manner; Msk1 predominantly regulates Atxn1 in the cerebellum, while Rsk3 is the predominant regulator of Atxn1 in the brainstem. Our results demonstrate that toxic protein levels can be modulated by different regulators in select brain regions, and hence targeting multiple regulators can expand therapeutic efficacy to rescue multiple degenerating brain areas.

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Dual targeting of brain region-specific kinases potentiates neurological rescue in Spinocerebellar ataxia type 1

Project description:Dual targeting of brain region-specific kinases potentiates neurological rescue in Spinocerebellar ataxia type 1

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