Identification of a novel interaction of FUS and syntaphilin may explain synaptic and mitochondrial abnormalities caused by ALS mutations

Abstract Aberrantly expressed fused in sarcoma (FUS) is a hallmark of FUS-related amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Wildtype FUS localises to synapses and interacts with mitochondrial proteins while mutations have been shown to cause to pathological changes affec...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Shaakir Salam, Sara Tacconelli, Bradley N. Smith, Jacqueline C. Mitchell, Elizabeth Glennon, Nikolas Nikolaou, Corinne Houart, Caroline Vance
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/0579a38085794fbda811e7a5e4c1c5ce
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:0579a38085794fbda811e7a5e4c1c5ce
record_format	dspace
spelling	oai:doaj.org-article:0579a38085794fbda811e7a5e4c1c5ce2021-12-02T14:33:58ZIdentification of a novel interaction of FUS and syntaphilin may explain synaptic and mitochondrial abnormalities caused by ALS mutations10.1038/s41598-021-93189-62045-2322https://doaj.org/article/0579a38085794fbda811e7a5e4c1c5ce2021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-93189-6https://doaj.org/toc/2045-2322Abstract Aberrantly expressed fused in sarcoma (FUS) is a hallmark of FUS-related amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Wildtype FUS localises to synapses and interacts with mitochondrial proteins while mutations have been shown to cause to pathological changes affecting mitochondria, synapses and the neuromuscular junction (NMJ). This indicates a crucial physiological role for FUS in regulating synaptic and mitochondrial function that is currently poorly understood. In this paper we provide evidence that mislocalised cytoplasmic FUS causes mitochondrial and synaptic changes and that FUS plays a vital role in maintaining neuronal health in vitro and in vivo. Overexpressing mutant FUS altered synaptic numbers and neuronal complexity in both primary neurons and zebrafish models. The degree to which FUS was mislocalised led to differences in the synaptic changes which was mirrored by changes in mitochondrial numbers and transport. Furthermore, we showed that FUS co-localises with the mitochondrial tethering protein Syntaphilin (SNPH), and that mutations in FUS affect this relationship. Finally, we demonstrated mutant FUS led to changes in global protein translation. This localisation between FUS and SNPH could explain the synaptic and mitochondrial defects observed leading to global protein translation defects. Importantly, our results support the ‘gain-of-function’ hypothesis for disease pathogenesis in FUS-related ALS.Shaakir SalamSara TacconelliBradley N. SmithJacqueline C. MitchellElizabeth GlennonNikolas NikolaouCorinne HouartCaroline VanceNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Shaakir Salam Sara Tacconelli Bradley N. Smith Jacqueline C. Mitchell Elizabeth Glennon Nikolas Nikolaou Corinne Houart Caroline Vance Identification of a novel interaction of FUS and syntaphilin may explain synaptic and mitochondrial abnormalities caused by ALS mutations
description	Abstract Aberrantly expressed fused in sarcoma (FUS) is a hallmark of FUS-related amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Wildtype FUS localises to synapses and interacts with mitochondrial proteins while mutations have been shown to cause to pathological changes affecting mitochondria, synapses and the neuromuscular junction (NMJ). This indicates a crucial physiological role for FUS in regulating synaptic and mitochondrial function that is currently poorly understood. In this paper we provide evidence that mislocalised cytoplasmic FUS causes mitochondrial and synaptic changes and that FUS plays a vital role in maintaining neuronal health in vitro and in vivo. Overexpressing mutant FUS altered synaptic numbers and neuronal complexity in both primary neurons and zebrafish models. The degree to which FUS was mislocalised led to differences in the synaptic changes which was mirrored by changes in mitochondrial numbers and transport. Furthermore, we showed that FUS co-localises with the mitochondrial tethering protein Syntaphilin (SNPH), and that mutations in FUS affect this relationship. Finally, we demonstrated mutant FUS led to changes in global protein translation. This localisation between FUS and SNPH could explain the synaptic and mitochondrial defects observed leading to global protein translation defects. Importantly, our results support the ‘gain-of-function’ hypothesis for disease pathogenesis in FUS-related ALS.
format	article
author	Shaakir Salam Sara Tacconelli Bradley N. Smith Jacqueline C. Mitchell Elizabeth Glennon Nikolas Nikolaou Corinne Houart Caroline Vance
author_facet	Shaakir Salam Sara Tacconelli Bradley N. Smith Jacqueline C. Mitchell Elizabeth Glennon Nikolas Nikolaou Corinne Houart Caroline Vance
author_sort	Shaakir Salam
title	Identification of a novel interaction of FUS and syntaphilin may explain synaptic and mitochondrial abnormalities caused by ALS mutations
title_short	Identification of a novel interaction of FUS and syntaphilin may explain synaptic and mitochondrial abnormalities caused by ALS mutations
title_full	Identification of a novel interaction of FUS and syntaphilin may explain synaptic and mitochondrial abnormalities caused by ALS mutations
title_fullStr	Identification of a novel interaction of FUS and syntaphilin may explain synaptic and mitochondrial abnormalities caused by ALS mutations
title_full_unstemmed	Identification of a novel interaction of FUS and syntaphilin may explain synaptic and mitochondrial abnormalities caused by ALS mutations
title_sort	identification of a novel interaction of fus and syntaphilin may explain synaptic and mitochondrial abnormalities caused by als mutations
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/0579a38085794fbda811e7a5e4c1c5ce
work_keys_str_mv	AT shaakirsalam identificationofanovelinteractionoffusandsyntaphilinmayexplainsynapticandmitochondrialabnormalitiescausedbyalsmutations AT saratacconelli identificationofanovelinteractionoffusandsyntaphilinmayexplainsynapticandmitochondrialabnormalitiescausedbyalsmutations AT bradleynsmith identificationofanovelinteractionoffusandsyntaphilinmayexplainsynapticandmitochondrialabnormalitiescausedbyalsmutations AT jacquelinecmitchell identificationofanovelinteractionoffusandsyntaphilinmayexplainsynapticandmitochondrialabnormalitiescausedbyalsmutations AT elizabethglennon identificationofanovelinteractionoffusandsyntaphilinmayexplainsynapticandmitochondrialabnormalitiescausedbyalsmutations AT nikolasnikolaou identificationofanovelinteractionoffusandsyntaphilinmayexplainsynapticandmitochondrialabnormalitiescausedbyalsmutations AT corinnehouart identificationofanovelinteractionoffusandsyntaphilinmayexplainsynapticandmitochondrialabnormalitiescausedbyalsmutations AT carolinevance identificationofanovelinteractionoffusandsyntaphilinmayexplainsynapticandmitochondrialabnormalitiescausedbyalsmutations
_version_	1718391111909638144

Identification of a novel interaction of FUS and syntaphilin may explain synaptic and mitochondrial abnormalities caused by ALS mutations

Ejemplares similares