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MicroRNA-16 targets mRNA involved in neurite extension and branching in hippocampal neurons during presymptomatic prion disease.
Neurobiol Dis. 2018 04; 112:1-13.ND

Abstract

The mechanisms that lead to neuronal death in neurodegenerative diseases are poorly understood. Prion diseases, like many more common disorders such as Alzheimer's and Parkinson's diseases, are characterized by the progressive accumulation of misfolded disease-specific proteins. The earliest changes observed in brain tissue include a reduction in synaptic number and retraction of dendritic spines, followed by reduced length and branching of neurites. These pathologies are observable during presymptomatic stages of disease and are accompanied by altered expression of transcripts that include miRNAs. Here we report that miR-16 localized within hippocampal CA1 neurons is increased during early prion disease. Modulating miR-16 expression in mature murine hippocampal neurons by expression from a lentivirus, thus mimicking the modest increase seen in vivo, was found to induce neurodegeneration. This was characterized by retraction of neurites and reduced branching. We performed immunoprecipitation of the miR-16 enriched RISC complex, and identified associated transcripts from the co-immunoprecipitated RNA (Ago2 RIP-Chip). These transcripts were enriched with predicted binding sites for miR-16, including the validated miR-16 targets APP and BCL2, as well as numerous novel targets. In particular, genes within the neurotrophin receptor mediated MAPK/ERK pathway were potentially regulated by miR-16; including TrkB (NTRK2), MEK1 (MAP2K1) and c-Raf (RAF). Increased miR-16 expression in neurons during presymptomatic prion disease and reduction in proteins involved in MAPK/ERK signaling represents a possible mechanism by which neurite length and branching are decreased during early stages of disease.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Burak K
Zoonotic Diseases and Special Pathogens, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada; Department of Medical Microbiology and Infectious Diseases, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
Lamoureux L
Zoonotic Diseases and Special Pathogens, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada.
Boese A
Zoonotic Diseases and Special Pathogens, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada; Department of Medical Microbiology and Infectious Diseases, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
Majer A
Zoonotic Diseases and Special Pathogens, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada; Department of Medical Microbiology and Infectious Diseases, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
Saba R
Zoonotic Diseases and Special Pathogens, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada.
Niu Y
Zoonotic Diseases and Special Pathogens, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada.
Frost K
Zoonotic Diseases and Special Pathogens, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada.
Booth SA
Zoonotic Diseases and Special Pathogens, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada; Department of Medical Microbiology and Infectious Diseases, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada. Electronic address: Stephanie.Booth@canada.ca.

MeSH

AnimalsAsymptomatic DiseasesCells, CulturedFemaleGene Regulatory NetworksHippocampusMiceMicroRNAsNeuritesNeuronsPregnancyPrion DiseasesRNA, Messenger

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29277556

Citation

Burak, Kristyn, et al. "MicroRNA-16 Targets mRNA Involved in Neurite Extension and Branching in Hippocampal Neurons During Presymptomatic Prion Disease." Neurobiology of Disease, vol. 112, 2018, pp. 1-13.
Burak K, Lamoureux L, Boese A, et al. MicroRNA-16 targets mRNA involved in neurite extension and branching in hippocampal neurons during presymptomatic prion disease. Neurobiol Dis. 2018;112:1-13.
Burak, K., Lamoureux, L., Boese, A., Majer, A., Saba, R., Niu, Y., Frost, K., & Booth, S. A. (2018). MicroRNA-16 targets mRNA involved in neurite extension and branching in hippocampal neurons during presymptomatic prion disease. Neurobiology of Disease, 112, 1-13. https://doi.org/10.1016/j.nbd.2017.12.011
Burak K, et al. MicroRNA-16 Targets mRNA Involved in Neurite Extension and Branching in Hippocampal Neurons During Presymptomatic Prion Disease. Neurobiol Dis. 2018;112:1-13. PubMed PMID: 29277556.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - MicroRNA-16 targets mRNA involved in neurite extension and branching in hippocampal neurons during presymptomatic prion disease. AU - Burak,Kristyn, AU - Lamoureux,Lise, AU - Boese,Amrit, AU - Majer,Anna, AU - Saba,Reuben, AU - Niu,Yulian, AU - Frost,Kathy, AU - Booth,Stephanie A, Y1 - 2017/12/22/ PY - 2017/06/20/received PY - 2017/11/14/revised PY - 2017/12/19/accepted PY - 2017/12/27/pubmed PY - 2019/9/7/medline PY - 2017/12/27/entrez KW - Ago2 RIP-Chip KW - MAPK/ERK signaling KW - Neurite KW - Neurodegeneration KW - Presymptomatic disease KW - Prion KW - miR-16 KW - microRNA targets SP - 1 EP - 13 JF - Neurobiology of disease JO - Neurobiol Dis VL - 112 N2 - The mechanisms that lead to neuronal death in neurodegenerative diseases are poorly understood. Prion diseases, like many more common disorders such as Alzheimer's and Parkinson's diseases, are characterized by the progressive accumulation of misfolded disease-specific proteins. The earliest changes observed in brain tissue include a reduction in synaptic number and retraction of dendritic spines, followed by reduced length and branching of neurites. These pathologies are observable during presymptomatic stages of disease and are accompanied by altered expression of transcripts that include miRNAs. Here we report that miR-16 localized within hippocampal CA1 neurons is increased during early prion disease. Modulating miR-16 expression in mature murine hippocampal neurons by expression from a lentivirus, thus mimicking the modest increase seen in vivo, was found to induce neurodegeneration. This was characterized by retraction of neurites and reduced branching. We performed immunoprecipitation of the miR-16 enriched RISC complex, and identified associated transcripts from the co-immunoprecipitated RNA (Ago2 RIP-Chip). These transcripts were enriched with predicted binding sites for miR-16, including the validated miR-16 targets APP and BCL2, as well as numerous novel targets. In particular, genes within the neurotrophin receptor mediated MAPK/ERK pathway were potentially regulated by miR-16; including TrkB (NTRK2), MEK1 (MAP2K1) and c-Raf (RAF). Increased miR-16 expression in neurons during presymptomatic prion disease and reduction in proteins involved in MAPK/ERK signaling represents a possible mechanism by which neurite length and branching are decreased during early stages of disease. SN - 1095-953X UR - https://www.unboundmedicine.com/medline/citation/29277556/MicroRNA_16_targets_mRNA_involved_in_neurite_extension_and_branching_in_hippocampal_neurons_during_presymptomatic_prion_disease_ DB - PRIME DP - Unbound Medicine ER -