Disruption of a miR-29 binding site leading toCOL4A1upregulation causes pontine autosomal dominant microangiopathy with leukoencephalopathy

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Abstract

Cerebral small vessel disease (cSVD) is a heterogeneous group of disorders. Screening of known cSVD genes identifies the causative mutation in <15% of familial cSVD cases. We sought to identify novel causes of cSVD.

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Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis.

Eva van Rooij, Lillian Sutherland, Jeffrey Thatcher … (2008)

Acute myocardial infarction (MI) due to coronary artery occlusion is accompanied by a pathological remodeling response that includes hypertrophic cardiac growth and fibrosis, which impair cardiac contractility. Previously, we showed that cardiac hypertrophy and heart failure are accompanied by characteristic changes in the expression of a collection of specific microRNAs (miRNAs), which act as negative regulators of gene expression. Here, we show that MI in mice and humans also results in the dysregulation of specific miRNAs, which are similar to but distinct from those involved in hypertrophy and heart failure. Among the MI-regulated miRNAs are members of the miR-29 family, which are down-regulated in the region of the heart adjacent to the infarct. The miR-29 family targets a cadre of mRNAs that encode proteins involved in fibrosis, including multiple collagens, fibrillins, and elastin. Thus, down-regulation of miR-29 would be predicted to derepress the expression of these mRNAs and enhance the fibrotic response. Indeed, down-regulation of miR-29 with anti-miRs in vitro and in vivo induces the expression of collagens, whereas over-expression of miR-29 in fibroblasts reduces collagen expression. We conclude that miR-29 acts as a regulator of cardiac fibrosis and represents a potential therapeutic target for tissue fibrosis in general.

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TGF-β/Smad3 signaling promotes renal fibrosis by inhibiting miR-29.

Wei Qin, Arthur Chung, Xiao R. Huang … (2011)

TGF-β/Smad3 signaling promotes fibrosis, but the development of therapeutic interventions involving this pathway will require the identification and ultimate targeting of downstream fibrosis-specific genes. In this study, using a microRNA microarray and real-time PCR, wild-type mice had reduced expression of miR-29 along with the development of progressive renal fibrosis in obstructive nephropathy. In contrast, Smad3 knockout mice had increased expression of miR-29 along with the absence of renal fibrosis in the same model of obstruction. In cultured fibroblasts and tubular epithelial cells, Smad3 mediated TGF-β(1)-induced downregulation of miR-29 by binding to the promoter of miR-29. Furthermore, miR-29 acted as a downstream inhibitor and therapeutic microRNA for TGF-β/Smad3-mediated fibrosis. In vitro, overexpression of miR-29b inhibited, but knockdown of miR-29 enhanced, TGF-β(1)-induced expression of collagens I and III by renal tubular cells. Ultrasound-mediated gene delivery of miR-29b either before or after established obstructive nephropathy blocked progressive renal fibrosis. In conclusion, miR-29 is a downstream inhibitor of TGF-β/Smad3-mediated fibrosis and may have therapeutic potential for diseases involving fibrosis.

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COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets

Debbie S. Kuo, Cassandre Labelle-Dumais, Douglas B. Gould (2012)

Heterotrimers composed of collagen type IV alpha 1 (COL4A1) and alpha 2 (COL4A2) constitute one of the most abundant components of nearly all basement membranes. Accordingly, mutations in COL4A1 or COL4A2 are pleiotropic and contribute to a broad spectrum of disorders, including myopathy, glaucoma and hemorrhagic stroke. Here, we summarize the contributions of COL4A1 and COL4A2 mutations in human disease, integrate knowledge gained from model organisms and evaluate the implications for pathogenic mechanisms and therapeutic approaches.

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Author and article information

Journal

Title: Annals of Neurology

Abbreviated Title: Ann Neurol.

Publisher: Wiley

ISSN: 03645134

Publication date Created: November 2016

Publication date (Print): November 2016

Publication date (Electronic): October 19 2016

Volume: 80

Issue: 5

Pages: 741-753

Affiliations

[1 ]Inserm U1161; Genetics and Physiopathology of Cerebrovascular Diseases; Paris France

[2 ]Inserm U1161; Paris7 Diderot University, Sorbonne Paris Cité; Paris France

[3 ]AP-HP Lariboisière Neurology Department; CERVCO Reference Center for Rare Vascular Diseases of the Eye and Brain; Paris France

[4 ]Neurology department, CHRU of Lille, Lille 2 University, Inserm U1171; Lille France

[5 ]AP-HP Lariboisière Molecular Genetics Department; CERVCO Reference Center for Rare Vascular Diseases of the Eye and Brain; Paris France

[6 ]Neurology Department; Saint Philibert Hospital; Lomme France

[7 ]Neurology Department; Gonesse Hospital; Gonesse France

[8 ]Neurology Department; Henri Mondor Hospital; Creteil France

[9 ]Neurology Department; Valenciennes Hospital; Valenciennes France

[10 ]Neurology Department; Coulommiers Hospital; Coulommiers France

[11 ]Institute of Neuropathology; University Medical Center; Hamburg Germany

[12 ]Department of Neurology; University Hospital Schleswig-Holstein; Kiel Germany

[13 ]Neurology Department; Agen Hospital; Agen France

[14 ]CMAbio3, Applied Microscopy and Biology Center; University of Caen; Caen France

[15 ]Institute of Cardiovascular and Medical Sciences; College of Medical, Veterinary and Life Sciences, University of Glasgow; Glasgow United Kingdom

[16 ]Pathology Department; CHRU of Caen, University of Caen Normandy; Inserm U1075

Article

DOI: 10.1002/ana.24782

PubMed ID: 27666438

SO-VID: 90eb77ed-5c14-4486-913e-1efdec660299

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http://doi.wiley.com/10.1002/tdm_license_1.1

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Disruption of a miR-29 binding site leading toCOL4A1upregulation causes pontine autosomal dominant microangiopathy with leukoencephalopathy : COL4A1Upregulation in PADMAL

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Most cited references 12

Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis.

TGF-β/Smad3 signaling promotes renal fibrosis by inhibiting miR-29.

COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets

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