Modulation of miR-181 influences dopaminergic neuronal degeneration in a mouse model of Parkinson's disease

Colleen S. Stein; Jared M. McLendon; Nathan H. Witmer; Ryan L. Boudreau

doi:10.1016/j.omtn.2022.02.007

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Modulation of miR-181 influences dopaminergic neuronal degeneration in a mouse model of Parkinson's disease

Journal article

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Modulation of miR-181 influences dopaminergic neuronal degeneration in a mouse model of Parkinson's disease

Colleen S. Stein, Jared M. McLendon, Nathan H. Witmer and Ryan L. Boudreau

Molecular therapy. Nucleic acids, Vol.28, pp.1-15

06/14/2022

DOI: 10.1016/j.omtn.2022.02.007

PMCID: PMC8899134

PMID: 35280925

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Abstract

Parkinson's disease (PD) is caused by the loss of dopaminergic (DA) neurons in the substantia nigra (SN). Although PD pathogenesis is not fully understood, studies implicate perturbations in gene regulation, mitochondrial function, and neuronal activity. MicroRNAs (miRs) are small gene regulatory RNAs that inhibit diverse subsets of target mRNAs, and several studies have noted miR expression alterations in PD brains. For example, miR-181a is abundant in the brain and is increased in PD patient brain samples; however, the disease relevance of this remains unclear. Here, we show that miR181 target mRNAs are broadly downregulated in aging and PD brains. To address whether the miR-181 family plays a role in PD pathogenesis, we generated adeno-associated viruses (AAVs) to overexpress and inhibit the miR-181 isoforms. After co-injection with AAV overexpressing alpha-synuclein (aSyn) into mouse SN (PD model), we found that moderate miRloss, whereas miR-181 inhibition was neuroprotective relative to controls (GFP alone and/or scrambled RNA). Also, prolonged miR-181 overexpression in SN alone elicited measurable neurotoxicity that is coincident with an increased immune response. mRNA-seq analyses revealed that miR-181a/b inhibits genes involved in synaptic transmission, neurite outgrowth, and mitochondrial respiration, along with several genes having known protective roles and genetic links in PD.

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Medicine, Research & Experimental

Research & Experimental Medicine

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Details

Title: Subtitle: Modulation of miR-181 influences dopaminergic neuronal degeneration in a mouse model of Parkinson's disease
Creators: Colleen S. Stein - University of Iowa
Jared M. McLendon - University of Iowa
Nathan H. Witmer - University of Iowa
Ryan L. Boudreau - University of Iowa
Resource Type: Journal article
Publication Details: Molecular therapy. Nucleic acids, Vol.28, pp.1-15
DOI: 10.1016/j.omtn.2022.02.007
PMID: 35280925
PMCID: PMC8899134
NLM abbreviation: Mol Ther Nucleic Acids
ISSN: 2162-2531
eISSN: 2162-2531
Publisher: Elsevier
Number of pages: 15
Grant note: HL148796 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA HL007121 / Abboud Cardiovascular Research Center NIH T32 Iowa Neuroscience Institute Accelerator Award (University of Iowa) Michael J. Fox Foundation for Parkinson's Research Roy J. Carver Trust (University of Iowa)
Language: English
Date published: 06/14/2022
Academic Unit: Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
Record Identifier: 9984618515702771

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