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MicroRNA abundance is altered in synaptoneurosomes during prion disease
Amrit S Boese1, Reuben Saba2, Kristyn Campbell1
1Molecular PathoBiology, Public Health Agency of Canada, National Microbiology Laboratory, 1015 Arlington St., Winnipeg, MB R3E 3R2, Canada; Department of Medical Microbiology and Infectious Diseases, Faculty of Health Sciences, University of Manitoba, 730 William Ave., Winnipeg, MB R3E 0W3, Canada.
Abstract:
Discrepancy in synaptic structural plasticity is one of the earliest manifestations of the neurodegenerative state. In prion diseases, a reduction in synapses and dendritic spine densities is observed during preclinical disease in neurons of the cortex and hippocampus. The underlying molecular mechanisms of these alterations have not been identified but microRNAs (miRNAs), many of which are enriched at the synapse, likely regulate local protein synthesis in rapid response to stressors such as replicating prions. MiRNAs are therefore candidate regulators of these early neurodegenerative changes and may provide clues as to the molecular pathways involved. We therefore determined changes in mature miRNA abundance within synaptoneurosomes isolated from prion-infected, as compared to mock-infected animals, at asymptomatic and symptomatic stages of disease. During preclinical disease, miRNAs that are enriched in neurons including miR-124a-3p, miR-136-5p and miR-376a-3p were elevated. At later stages of disease we found increases in miRNAs that have previously been identified as deregulated in brain tissues of prion infected mice, as well as in Alzheimer's disease (AD) models. These include miR-146a-5p, miR-142-3p, miR-143-3p, miR-145a-5p, miR-451a, miR-let-7b, miR-320 and miR-150-5p. A number of miRNAs also decreased in abundance during clinical disease. These included almost all members of the related miR-200 family (miR-200a-3p, miR-200b-3p, miR-200c-3p, miR-141-3p, and miR-429-3p) and the 182 cluster (miR-182-5p and miR-183-5p).
Insights
MicroRNAs (miRNAs) change in prion disease, impacting synaptic plasticity early. Specific miRNAs increase during preclinical stages and later disease, while others decrease, offering insights into neurodegeneration.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Synaptic structural plasticity alterations are early signs of neurodegeneration, notably reduced synapses and dendritic spines in prion diseases.
- MicroRNAs (miRNAs), abundant at synapses, are potential regulators of local protein synthesis and early neurodegenerative changes.
- Understanding miRNA regulation is crucial for identifying molecular pathways involved in prion disease pathogenesis.
Purpose of the Study:
- To investigate changes in mature miRNA abundance in synaptoneurosomes during prion disease progression.
- To identify specific miRNAs associated with early and late stages of prion-induced neurodegeneration.
- To explore the role of miRNAs in synaptic alterations during prion diseases.
Main Methods:
- Isolation of synaptoneurosomes from prion-infected and mock-infected animal models.
- Quantitative analysis of mature miRNA abundance at asymptomatic and symptomatic disease stages.
- Comparison of miRNA profiles between healthy and prion-diseased subjects.
Main Results:
- Neuronal miRNAs (miR-124a-3p, miR-136-5p, miR-376a-3p) were elevated during preclinical prion disease.
- Several miRNAs (miR-146a-5p, miR-142-3p, miR-143-3p, miR-145a-5p, miR-451a, miR-let-7b, miR-320, miR-150-5p) increased in later disease stages.
- Specific miRNA families (miR-200, miR-182 cluster) showed decreased abundance during clinical prion disease.
Conclusions:
- MiRNA dysregulation is a significant feature of prion disease, occurring early and evolving with disease progression.
- Altered miRNA profiles correlate with synaptic changes and neurodegeneration in prion diseases.
- These findings highlight miRNAs as potential biomarkers and therapeutic targets for prion-related neurodegenerative disorders.
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