Huntingtin Aggregation Impairs Autophagy, Leading to Argonaute-2 Accumulation and Global MicroRNA Dysregulation.

Pircs K, Petri R, Madsen S, Brattås PL, Vuono R, Ottosson DR, St-Amour I, Hersbach BA, Matusiak-Brückner M, Lundh SH, Petersén Å, Déglon N, Hébert SS, Parmar M, Barker RA, Jakobsson J

Cell Rep 24 (6) 1397-1406 [2018-08-07; online 2018-08-09]

Many neurodegenerative diseases are characterized by the presence of intracellular protein aggregates, resulting in alterations in autophagy. However, the consequences of impaired autophagy for 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.

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NGI Stockholm (Genomics Applications) [Service]

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PubMed 30089251

DOI 10.1016/j.celrep.2018.07.017

Crossref 10.1016/j.celrep.2018.07.017

S2211-1247(18)31107-0

GEO GSE78928 [Huntingtin aggregation impairs autophagy leading to Argonaute-2 accumulation and global microRNA dysregulation]