Profiling of Argonaute-2-loaded microRNAs in a mouse model of frontotemporal dementia with parkinsonism-17

International Journal of Physiology, Pathophysiology and Pharmacology

Félix Hernández¹  Aidan Kenny²  José J Lucas³  Jesús Avila⁴ 

[1] Department of Molecular Neuropathology, Centro de Biologa Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientficas (CSIC), Universidad Autnoma de Madrid (UAM), Centro Investigacin Biomdica en Red Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain;Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland;Discipline of Physiology, School of Medicine, Trinity College Dublin, The University of Dublin, Dublin 2, Ireland;FutureNeuro Research Centre, Dublin 2, Ireland

关键词: Tauopathy;    frontotemporal dementia with parkinsonism-17;    MicroRNA;    Argonaute-2;   

DOI  :  

学科分类：生理学与病理学

来源: e-Century Publishing Corporation

【 摘 要 】

Tauopathies are a group of neurodegenerative diseases characterized by the pathological aggregation of the microtubule-associated protein tau. These include more than 20 diseases, with Alzheimer’s disease being the most frequent. While pathological and neurotoxic effects of tau are well documented, the mechanisms by which tau can promote neurodegeneration are less clear. Increasing evidence suggests a functional role for microRNAs in the pathogenesis of tauopathies, with altered expression and function of microRNAs in experimental models and patient brain. To determine whether a pathological expression of tau leads to altered microRNA expression, we investigated a mouse model (VLW), which overexpresses tau carrying three mutations identified in patients suffering from frontotemporal dementia with parkinsonism-17. Argonaute-2-bound microRNAs were co-immunoprecipitated using hippocampal tissue to identify active microRNAs within the model and quantified using a genome-wide high-throughput qPCR-based microRNA platform. While similar numbers of microRNAs are present between wild-type and VLW mice, a prominent increase in Argonaute-2-bound levels of microRNAs could be observed in VLW mice. This included microRNA-134, microRNA-99a and microRNA-101. Subsequent experiments revealed this increase in Argonaute-2 loading of microRNAs to correlate with increased microRNA expression. Our in vivo study suggests that a pathological tau overexpression may lead to an increase in active microRNAs, possibly contributing to dysregulation of gene expression and tau-induced pathology.

【 授权许可】

CC BY-NC