Cell-type specific differences in promoter activity of the ALS-linked C9orf72 mouse ortholog

Abstract A hexanucleotide repeat expansion in the C9orf72 gene is the most common cause of inherited forms of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Both loss-of-function and gain-of-function mechanisms have been proposed to underlie this disease, but the pathogenic pathw...

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Autores principales:	Abraham J. Langseth, Juhyun Kim, Janet E. Ugolino, Yajas Shah, Ho-Yon Hwang, Jiou Wang, Dwight E. Bergles, Solange P. Brown
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/3274edd052924b6ca7774bbd1462a817
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spelling	oai:doaj.org-article:3274edd052924b6ca7774bbd1462a8172021-12-02T12:32:00ZCell-type specific differences in promoter activity of the ALS-linked C9orf72 mouse ortholog10.1038/s41598-017-05864-22045-2322https://doaj.org/article/3274edd052924b6ca7774bbd1462a8172017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-05864-2https://doaj.org/toc/2045-2322Abstract A hexanucleotide repeat expansion in the C9orf72 gene is the most common cause of inherited forms of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Both loss-of-function and gain-of-function mechanisms have been proposed to underlie this disease, but the pathogenic pathways are not fully understood. To better understand the involvement of different cell types in the pathogenesis of ALS, we systematically analyzed the distribution of promoter activity of the mouse ortholog of C9orf72 in the central nervous system. We demonstrate that C9orf72 promoter activity is widespread in both excitatory and inhibitory neurons as well as in oligodendrocytes and oligodendrocyte precursor cells. In contrast, few microglia and astrocytes exhibit detectable C9orf72 promoter activity. Although at a gross level, the distribution of C9orf72 promoter activity largely follows overall cellular density, we found that it is selectively enriched in subsets of neurons and glial cells that degenerate in ALS. Specifically, we show that C9orf72 promoter activity is enriched in corticospinal and spinal motor neurons as well as in oligodendrocytes in brain regions that are affected in ALS. These results suggest that cell autonomous changes in both neurons and glia may contribute to C9orf72-mediated disease, as has been shown for mutations in superoxide dismutase-1 (SOD1).Abraham J. LangsethJuhyun KimJanet E. UgolinoYajas ShahHo-Yon HwangJiou WangDwight E. BerglesSolange P. BrownNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Abraham J. Langseth Juhyun Kim Janet E. Ugolino Yajas Shah Ho-Yon Hwang Jiou Wang Dwight E. Bergles Solange P. Brown Cell-type specific differences in promoter activity of the ALS-linked C9orf72 mouse ortholog
description	Abstract A hexanucleotide repeat expansion in the C9orf72 gene is the most common cause of inherited forms of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Both loss-of-function and gain-of-function mechanisms have been proposed to underlie this disease, but the pathogenic pathways are not fully understood. To better understand the involvement of different cell types in the pathogenesis of ALS, we systematically analyzed the distribution of promoter activity of the mouse ortholog of C9orf72 in the central nervous system. We demonstrate that C9orf72 promoter activity is widespread in both excitatory and inhibitory neurons as well as in oligodendrocytes and oligodendrocyte precursor cells. In contrast, few microglia and astrocytes exhibit detectable C9orf72 promoter activity. Although at a gross level, the distribution of C9orf72 promoter activity largely follows overall cellular density, we found that it is selectively enriched in subsets of neurons and glial cells that degenerate in ALS. Specifically, we show that C9orf72 promoter activity is enriched in corticospinal and spinal motor neurons as well as in oligodendrocytes in brain regions that are affected in ALS. These results suggest that cell autonomous changes in both neurons and glia may contribute to C9orf72-mediated disease, as has been shown for mutations in superoxide dismutase-1 (SOD1).
format	article
author	Abraham J. Langseth Juhyun Kim Janet E. Ugolino Yajas Shah Ho-Yon Hwang Jiou Wang Dwight E. Bergles Solange P. Brown
author_facet	Abraham J. Langseth Juhyun Kim Janet E. Ugolino Yajas Shah Ho-Yon Hwang Jiou Wang Dwight E. Bergles Solange P. Brown
author_sort	Abraham J. Langseth
title	Cell-type specific differences in promoter activity of the ALS-linked C9orf72 mouse ortholog
title_short	Cell-type specific differences in promoter activity of the ALS-linked C9orf72 mouse ortholog
title_full	Cell-type specific differences in promoter activity of the ALS-linked C9orf72 mouse ortholog
title_fullStr	Cell-type specific differences in promoter activity of the ALS-linked C9orf72 mouse ortholog
title_full_unstemmed	Cell-type specific differences in promoter activity of the ALS-linked C9orf72 mouse ortholog
title_sort	cell-type specific differences in promoter activity of the als-linked c9orf72 mouse ortholog
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/3274edd052924b6ca7774bbd1462a817
work_keys_str_mv	AT abrahamjlangseth celltypespecificdifferencesinpromoteractivityofthealslinkedc9orf72mouseortholog AT juhyunkim celltypespecificdifferencesinpromoteractivityofthealslinkedc9orf72mouseortholog AT janeteugolino celltypespecificdifferencesinpromoteractivityofthealslinkedc9orf72mouseortholog AT yajasshah celltypespecificdifferencesinpromoteractivityofthealslinkedc9orf72mouseortholog AT hoyonhwang celltypespecificdifferencesinpromoteractivityofthealslinkedc9orf72mouseortholog AT jiouwang celltypespecificdifferencesinpromoteractivityofthealslinkedc9orf72mouseortholog AT dwightebergles celltypespecificdifferencesinpromoteractivityofthealslinkedc9orf72mouseortholog AT solangepbrown celltypespecificdifferencesinpromoteractivityofthealslinkedc9orf72mouseortholog
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Cell-type specific differences in promoter activity of the ALS-linked C9orf72 mouse ortholog

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