MicroRNAs in ALS: Defining Cell-Type Specific Expression, Developing Methods to Modulate MicroRNAs in vivo, and Identifying Novel Therapeutic Targets

<p>Amyotrophic lateral sclerosis (ALS) is an adult-onset, fatal neuromuscular disease with no adequate therapies. MicroRNAs (miRNAs) are dysregulated in a variety of disease states, suggesting that this newly discovered class of gene expression repressors may be viable therapeutic targets. A microarray of miRNA changes in ALS model SOD1G93A rodents identified 12 miRNAs as significantly changed. Six miRNAs tested in human ALS tissues were confirmed increased. Specifically, miR-155 was increased 5-fold in mice and 2-fold in human spinal cords. Generation of mice that express a GFP-tagged miRNA processing protein behind cell-type specific promoters allowed for the identification of miRNA expression patterns in various neural cell types. From this information, we focused on the role of miR-155 on glial cells and particularly on neuroinflammatory pathways in ALS. miR-155, miR-146a, and miR-142-5p were upregulated beginning in a mid-disease stage and were highly correlated with one another and with various neuroinflammatory mediators. To test miRNA inhibition in the central nervous system as a potential novel therapeutic, we developed oligonucleotide-based miRNA inhibitors (anti-miRs) that could inhibit miRNAs throughout the central nervous system and in the periphery. Anti-miR-155 caused global derepression of targets in peritoneal macrophages and, following intraventricular delivery, demonstrated widespread functional distribution in the brain and spinal cord. After treating SOD1G93A mice with anti-miR-155, we significantly extended survival by 10 days and disease duration by 15 days (38%) while a scrambled control anti-miR did not significantly improve survival or disease duration. Therefore, antisense oligonucleotides may be used to successfully inhibit miRNAs throughout the brain and spinal cord, and miR-155 is a promising new therapeutic target for human ALS.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Biology and Biomedical Sciences: Neurosciences

Year dc:date.available

2014

Author dc:creator

• Koval, Erica Danielle

Contributors dc:contributor

• Timothy M Miller

• ALS
• inflammation
• microRNA
• neurodegenerative

Language dc:language

English (en)

DOI

https://doi.org/10.7936/K73T9F7C

OAI identifier oai:identifier

oai:openscholarship.wustl.edu:etd-2313