Suchergebnisse

Oligodendrocyte progenitor cells (OPCs), which differentiate into myelinating oligodendrocytes during central nervous system (CNS) development, are the main proliferative cells in the adult brain. OPCs are conventionally considered a homogeneous population, particularly with respect to their electrophysiological properties, but this has been debated. We show, by using single-cell electrophysiological recordings, that OPCs start out as a homogeneous population, but become functionally heterogeneous, varying both within and between brain regions and with age. These electrophysiological changes in OPCs correlate with the differentiation potential of OPCs; thus, they may underlie the differentiational differences in OPCs between regions and likewise differentiation failure with age. ; We acknowledge the support of the Wellcome - MRC Cambridge Stem Cell Institute core facility managers, in particular for this work Dr Maike Paramor and Miss Victoria Murray with RNA sequencing, and all staff members of the University Biomedical Services (UBS). This project has received funding from: the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement No 771411; R.T.K, K.A.E); the Wellcome Trust, a Research Career Development Fellowship (R.T.K. and K.A.E. 091543/Z/10/Z) and a Studentship (102160/Z/13/Z; Y.K); The Paul G Allen Frontiers Group, Allen Distinguished Investigator Award (12076, R.T.K., D.K.V.); The Medical Research Council, a studentship (S.O.S.); The Gates Foundation, a Gates Scholarship (S.S.), The Biotechnology and Biological Sciences Research Council, a studentship (S.A.); Homerton College Cambridge, a Junior Research Fellowship (D.K.V); The UK MS Society, a Cambridge Myelin Repair Centre grant (50; R.T.K, O.D.F.); The Fonds de recherche du Québec-Santé, a scholarship (Y.K.); The Cambridge Commonwealth European & International Trust, a scholarship (Y.K.); and the Lister Institute, a Research Prize (R.T.K., K.A.E, SOS).

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).