Huntingtin aggregation impairs autophagy leading to Argonaute-2 accumulation and global microRNA dysregulation
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Barker, R., & Vuono, R. (2018). Huntingtin aggregation impairs autophagy leading to Argonaute-2 accumulation and global microRNA dysregulation. Cell Reports, 24 (6), 1397-1406. https://doi.org/10.1016/j.celrep.2018.07.017
Many neurodegenerative diseases are characterized by the presence of intracellular protein aggregates resulting in alterations in autophagy. However, the consequences of impaired autophagy on neuronal function remain poorly understood. In this study, we used cell culture and mouse models of huntingtin protein aggregation, as well as post-mortem material from patients with Huntington’s disease to demonstrate that Argonaute-2 (AGO2) accumulates in the presence of neuronal protein aggregates and that this is due to impaired autophagy. Accumulation of AGO2, a key factor of the RNA-induced silencing complex that executes microRNA functions, results in global alterations of microRNA levels and activity. Together these results demonstrate that impaired autophagy found in neurodegenerative diseases not only influences protein aggregation, but also directly contributes to global alterations of intracellular post-transcriptional networks.
The work was supported by grants from the Swedish Research Council (# K2014-62X-22527-01-3 and K2014-62X-20404-08-5), the Swedish Foundation for Strategic Research (# FFL12-0074), the Swedish Brain Foundation (# FO2014-0106); the Swedish excellence project Basal Ganglia Disorders Linnaeus Consortium (Bagadilico), and the Swedish Government Initiative for Strategic Research Areas (MultiPark & StemTherapy).
Medical Research Council (MC_PC_12009)
External DOI: https://doi.org/10.1016/j.celrep.2018.07.017
This record's URL: https://www.repository.cam.ac.uk/handle/1810/287135
Attribution-NonCommercial-NoDerivatives 4.0 International
Licence URL: http://creativecommons.org/licenses/by-nc-nd/4.0/
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