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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Abstract

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. Pircs et al. report that aggregation of the mutant huntingtin protein, a hallmark of Huntington's disease proteinopathy, impairs macroautophagy, leading to Argonaute-2 accumulation and global dysregulation of microRNAs. These results indicate that autophagy not only influences protein aggregation but also directly contributes to the global alterations of post-transcriptional networks in Huntington's disease.

Detaljer

Författare
Enheter & grupper
Externa organisationer
  • University of Cambridge
  • Laval University
  • Lausanne University Hospital
  • Lund University
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Neurovetenskaper
  • Cell- och molekylärbiologi

Nyckelord

Originalspråkengelska
Sidor (från-till)1397-1406
Antal sidor10
TidskriftCell Reports
Volym24
Utgivningsnummer6
StatusPublished - 2018 aug
PublikationskategoriForskning
Peer review utfördJa