ESCRT-III Membrane Trafficking Misregulation Contributes To Fragile X Syndrome Synaptic Defects

Abstract The leading cause of heritable intellectual disability (ID) and autism spectrum disorders (ASD), Fragile X syndrome (FXS), is caused by loss of the mRNA-binding translational suppressor Fragile X Mental Retardation Protein (FMRP). In the Drosophila FXS disease model, we found FMRP binds shr...

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Autores principales:	Dominic J. Vita, Kendal Broadie
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/5a2afbeb68cf477ab4eeb358c269d558
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spelling	oai:doaj.org-article:5a2afbeb68cf477ab4eeb358c269d5582021-12-02T12:30:36ZESCRT-III Membrane Trafficking Misregulation Contributes To Fragile X Syndrome Synaptic Defects10.1038/s41598-017-09103-62045-2322https://doaj.org/article/5a2afbeb68cf477ab4eeb358c269d5582017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-09103-6https://doaj.org/toc/2045-2322Abstract The leading cause of heritable intellectual disability (ID) and autism spectrum disorders (ASD), Fragile X syndrome (FXS), is caused by loss of the mRNA-binding translational suppressor Fragile X Mental Retardation Protein (FMRP). In the Drosophila FXS disease model, we found FMRP binds shrub mRNA (human Chmp4) to repress Shrub expression, causing overexpression during the disease state early-use critical period. The FXS hallmark is synaptic overelaboration causing circuit hyperconnectivity. Testing innervation of a central brain learning/memory center, we found FMRP loss and Shrub overexpression similarly increase connectivity. The ESCRT-III core protein Shrub has a central role in endosome-to-multivesicular body membrane trafficking, with synaptic requirements resembling FMRP. Consistently, we found FMRP loss and Shrub overexpression similarly elevate endosomes and result in the arrested accumulation of enlarged intraluminal vesicles within synaptic boutons. Importantly, genetic correction of Shrub levels in the FXS model prevents synaptic membrane trafficking defects and strongly restores innervation. These results reveal a new molecular mechanism underpinning the FXS disease state.Dominic J. VitaKendal BroadieNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-18 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Dominic J. Vita Kendal Broadie ESCRT-III Membrane Trafficking Misregulation Contributes To Fragile X Syndrome Synaptic Defects
description	Abstract The leading cause of heritable intellectual disability (ID) and autism spectrum disorders (ASD), Fragile X syndrome (FXS), is caused by loss of the mRNA-binding translational suppressor Fragile X Mental Retardation Protein (FMRP). In the Drosophila FXS disease model, we found FMRP binds shrub mRNA (human Chmp4) to repress Shrub expression, causing overexpression during the disease state early-use critical period. The FXS hallmark is synaptic overelaboration causing circuit hyperconnectivity. Testing innervation of a central brain learning/memory center, we found FMRP loss and Shrub overexpression similarly increase connectivity. The ESCRT-III core protein Shrub has a central role in endosome-to-multivesicular body membrane trafficking, with synaptic requirements resembling FMRP. Consistently, we found FMRP loss and Shrub overexpression similarly elevate endosomes and result in the arrested accumulation of enlarged intraluminal vesicles within synaptic boutons. Importantly, genetic correction of Shrub levels in the FXS model prevents synaptic membrane trafficking defects and strongly restores innervation. These results reveal a new molecular mechanism underpinning the FXS disease state.
format	article
author	Dominic J. Vita Kendal Broadie
author_facet	Dominic J. Vita Kendal Broadie
author_sort	Dominic J. Vita
title	ESCRT-III Membrane Trafficking Misregulation Contributes To Fragile X Syndrome Synaptic Defects
title_short	ESCRT-III Membrane Trafficking Misregulation Contributes To Fragile X Syndrome Synaptic Defects
title_full	ESCRT-III Membrane Trafficking Misregulation Contributes To Fragile X Syndrome Synaptic Defects
title_fullStr	ESCRT-III Membrane Trafficking Misregulation Contributes To Fragile X Syndrome Synaptic Defects
title_full_unstemmed	ESCRT-III Membrane Trafficking Misregulation Contributes To Fragile X Syndrome Synaptic Defects
title_sort	escrt-iii membrane trafficking misregulation contributes to fragile x syndrome synaptic defects
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/5a2afbeb68cf477ab4eeb358c269d558
work_keys_str_mv	AT dominicjvita escrtiiimembranetraffickingmisregulationcontributestofragilexsyndromesynapticdefects AT kendalbroadie escrtiiimembranetraffickingmisregulationcontributestofragilexsyndromesynapticdefects
_version_	1718394337335705600

ESCRT-III Membrane Trafficking Misregulation Contributes To Fragile X Syndrome Synaptic Defects

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