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

Abraham J. Langseth, Juhyun Kim, Janet E. Ugolino, Yajas Shah, Ho-Yon Hwang, Jiou Wang, Dwight E Bergles, Solange P Brown

Research output: Contribution to journalArticle

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).

Original languageEnglish (US)
Article number5685
JournalScientific Reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017

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Amyotrophic Lateral Sclerosis
Oligodendroglia
Neurons
Neuroglia
Microglia
Motor Neurons
Astrocytes
Neurodegenerative Diseases
Central Nervous System
Mutation
Brain
Genes

ASJC Scopus subject areas

  • General

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Cell-Type specific differences in promoter activity of the ALS-linked C9orf72 mouse ortholog. / Langseth, Abraham J.; Kim, Juhyun; Ugolino, Janet E.; Shah, Yajas; Hwang, Ho-Yon; Wang, Jiou; Bergles, Dwight E; Brown, Solange P.

In: Scientific Reports, Vol. 7, No. 1, 5685, 01.12.2017.

Research output: Contribution to journalArticle

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AU - Shah, Yajas

AU - Hwang, Ho-Yon

AU - Wang, Jiou

AU - Bergles, Dwight E

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