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Acta Neuropathologica Communications

, 4:122

First Online: 18 November 2016Received: 08 November 2016Accepted: 09 November 2016

Abstract

Amyotrophic lateral sclerosis ALS is a progressive neurodegenerative disorder of upper and lower motor neurons. Mutations in the gene encoding the nuclear matrix protein Matrin 3 have been found in familial cases of ALS, as well as autosomal dominant distal myopathy with vocal cord and pharyngeal weakness. We previously found that spinal cord and muscle, organs involved in either ALS or distal myopathy, have relatively lower levels of Matrin 3 compared to the brain and other peripheral organs in the murine system. This suggests that these organs may be vulnerable to any changes in Matrin 3. In order to determine the role of Matrin 3 in these diseases, we created a transgenic mouse model for human wild-type Matrin 3 using the mouse prion promoter MoPrP on a FVB background.

We identified three founder transgenic lines that produced offspring in which mice developed either hindlimb paresis or paralysis with hindlimb and forelimb muscle atrophy. Muscles of affected mice showed a striking increase in nuclear Matrin 3, as well as the presence of rounded fibers, vacuoles, nuclear chains, and subsarcolemmal nuclei. Immunoblot analysis of the gastrocnemius muscle from phenotypic mice showed increased levels of Matrin 3 products migrating at approximately 120 doublet, 90, 70, and 55 kDa. While there was no significant change in the levels of Matrin 3 in the spinal cord in the phenotypic mice, the ventral horn contained individual cells with cytoplasmic redistribution of Matrin 3, as well as gliosis. The phenotypes of these mice indicate that dysregulation of Matrin 3 levels is deleterious to neuromuscular function.

KeywordsMatrin 3 Transgenic mouse model ALS Distal myopathy AbbreviationsALSAmyotrophic lateral sclerosis

BTXα-bungarotoxin

C9orf72Chromosome 9 open reading frame gene

FUSFused in sarcoma gene

IBMPFDInclusion body myopathy associated with Paget disease of bone and frontotemporal dementia

MATR3Matrin 3 gene

MATR3Matrin 3 protein

MMMild to moderate phenotype

MoPrPMouse prion promoter

NMJNeuromuscular junction

NTNon-transgenic

PBSPhosphate buffered saline

SSevere phenotype

SOD1Superoxide dismutase I gene

TARDBPTar-DNA binding protein gene

TBSTris-buffered saline

TDP-43TAR DNA binding protein 43

TgTransgenic

UTRUntranslated region

VCPValosin containing protein

VCPValosin containing protein gene

ZNP1Synaptotagmin 2

Electronic supplementary materialThe online version of this article doi:10.1186-s40478-016-0393-5 contains supplementary material, which is available to authorized users.

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Autor: Christina Moloney - Sruti Rayaprolu - John Howard - Susan Fromholt - Hilda Brown - Matt Collins - Mariela Cabrera - Colin 

Fuente: https://link.springer.com/







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