SRSF protein kinase 1 modulates RAN translation and suppresses CGG repeat toxicity

Abstract Transcribed CGG repeat expansions cause neurodegeneration in Fragile X‐associated tremor/ataxia syndrome (FXTAS). CGG repeat RNAs sequester RNA‐binding proteins (RBPs) into nuclear foci and undergo repeat‐associated non‐AUG (RAN) translation into toxic peptides. To identify proteins involve...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Indranil Malik, Yi‐Ju Tseng, Shannon E Wright, Kristina Zheng, Prithika Ramaiyer, Katelyn M Green, Peter K Todd
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	C9orf72 ALS CGG repeats FXTAS RAN translation SRSF Medicine (General) R5-920 Genetics QH426-470
Acceso en línea:	https://doaj.org/article/138cdabe97fa4b19802f057adaecf269
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:138cdabe97fa4b19802f057adaecf269
record_format	dspace
spelling	oai:doaj.org-article:138cdabe97fa4b19802f057adaecf2692021-11-08T09:27:45ZSRSF protein kinase 1 modulates RAN translation and suppresses CGG repeat toxicity1757-46841757-467610.15252/emmm.202114163https://doaj.org/article/138cdabe97fa4b19802f057adaecf2692021-11-01T00:00:00Zhttps://doi.org/10.15252/emmm.202114163https://doaj.org/toc/1757-4676https://doaj.org/toc/1757-4684Abstract Transcribed CGG repeat expansions cause neurodegeneration in Fragile X‐associated tremor/ataxia syndrome (FXTAS). CGG repeat RNAs sequester RNA‐binding proteins (RBPs) into nuclear foci and undergo repeat‐associated non‐AUG (RAN) translation into toxic peptides. To identify proteins involved in these processes, we employed a CGG repeat RNA‐tagging system to capture repeat‐associated RBPs by mass spectrometry in mammalian cells. We identified several SR (serine/arginine‐rich) proteins that interact selectively with CGG repeats basally and under cellular stress. These proteins modify toxicity in a Drosophila model of FXTAS. Pharmacologic inhibition of serine/arginine protein kinases (SRPKs), which alter SRSF protein phosphorylation, localization, and activity, directly inhibits RAN translation of CGG and GGGGCC repeats (associated with C9orf72 ALS/FTD) and triggers repeat RNA retention in the nucleus. Lowering SRPK expression suppressed toxicity in both FXTAS and C9orf72 ALS/FTD model flies, and SRPK inhibitors suppressed CGG repeat toxicity in rodent neurons. Together, these findings demonstrate roles for CGG repeat RNA binding proteins in RAN translation and repeat toxicity and support further evaluation of SRPK inhibitors in modulating RAN translation associated with repeat expansion disorders.Indranil MalikYi‐Ju TsengShannon E WrightKristina ZhengPrithika RamaiyerKatelyn M GreenPeter K ToddWileyarticleC9orf72 ALSCGG repeatsFXTASRAN translationSRSFMedicine (General)R5-920GeneticsQH426-470ENEMBO Molecular Medicine, Vol 13, Iss 11, Pp n/a-n/a (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	C9orf72 ALS CGG repeats FXTAS RAN translation SRSF Medicine (General) R5-920 Genetics QH426-470
spellingShingle	C9orf72 ALS CGG repeats FXTAS RAN translation SRSF Medicine (General) R5-920 Genetics QH426-470 Indranil Malik Yi‐Ju Tseng Shannon E Wright Kristina Zheng Prithika Ramaiyer Katelyn M Green Peter K Todd SRSF protein kinase 1 modulates RAN translation and suppresses CGG repeat toxicity
description	Abstract Transcribed CGG repeat expansions cause neurodegeneration in Fragile X‐associated tremor/ataxia syndrome (FXTAS). CGG repeat RNAs sequester RNA‐binding proteins (RBPs) into nuclear foci and undergo repeat‐associated non‐AUG (RAN) translation into toxic peptides. To identify proteins involved in these processes, we employed a CGG repeat RNA‐tagging system to capture repeat‐associated RBPs by mass spectrometry in mammalian cells. We identified several SR (serine/arginine‐rich) proteins that interact selectively with CGG repeats basally and under cellular stress. These proteins modify toxicity in a Drosophila model of FXTAS. Pharmacologic inhibition of serine/arginine protein kinases (SRPKs), which alter SRSF protein phosphorylation, localization, and activity, directly inhibits RAN translation of CGG and GGGGCC repeats (associated with C9orf72 ALS/FTD) and triggers repeat RNA retention in the nucleus. Lowering SRPK expression suppressed toxicity in both FXTAS and C9orf72 ALS/FTD model flies, and SRPK inhibitors suppressed CGG repeat toxicity in rodent neurons. Together, these findings demonstrate roles for CGG repeat RNA binding proteins in RAN translation and repeat toxicity and support further evaluation of SRPK inhibitors in modulating RAN translation associated with repeat expansion disorders.
format	article
author	Indranil Malik Yi‐Ju Tseng Shannon E Wright Kristina Zheng Prithika Ramaiyer Katelyn M Green Peter K Todd
author_facet	Indranil Malik Yi‐Ju Tseng Shannon E Wright Kristina Zheng Prithika Ramaiyer Katelyn M Green Peter K Todd
author_sort	Indranil Malik
title	SRSF protein kinase 1 modulates RAN translation and suppresses CGG repeat toxicity
title_short	SRSF protein kinase 1 modulates RAN translation and suppresses CGG repeat toxicity
title_full	SRSF protein kinase 1 modulates RAN translation and suppresses CGG repeat toxicity
title_fullStr	SRSF protein kinase 1 modulates RAN translation and suppresses CGG repeat toxicity
title_full_unstemmed	SRSF protein kinase 1 modulates RAN translation and suppresses CGG repeat toxicity
title_sort	srsf protein kinase 1 modulates ran translation and suppresses cgg repeat toxicity
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/138cdabe97fa4b19802f057adaecf269
work_keys_str_mv	AT indranilmalik srsfproteinkinase1modulatesrantranslationandsuppressescggrepeattoxicity AT yijutseng srsfproteinkinase1modulatesrantranslationandsuppressescggrepeattoxicity AT shannonewright srsfproteinkinase1modulatesrantranslationandsuppressescggrepeattoxicity AT kristinazheng srsfproteinkinase1modulatesrantranslationandsuppressescggrepeattoxicity AT prithikaramaiyer srsfproteinkinase1modulatesrantranslationandsuppressescggrepeattoxicity AT katelynmgreen srsfproteinkinase1modulatesrantranslationandsuppressescggrepeattoxicity AT peterktodd srsfproteinkinase1modulatesrantranslationandsuppressescggrepeattoxicity
_version_	1718442687066013696

SRSF protein kinase 1 modulates RAN translation and suppresses CGG repeat toxicity

Ejemplares similares