Suchergebnisse

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).

Direct neuronal reprogramming generates neurons to maintain the age of the starting somatic cell. Here, we describe a single vector-based method to generate induced neurons from dermal fibroblasts obtained from adult human donors. ; We thank Marie Persson Vejgården for technical assistance. The research leading to these results has received funding from the New York Stem Cell Foundation, the European Research Council under the European Union's Seventh Framework Programme: FP/2007-2013 Neuro Stem Cell Repair (no. 602278) and ERC Grant Agreement no. 30971, the Swedish Research Council (grant agreement 521-2012-5624, 2016-00873 and 70862601/ Bagadilico), Swedish Parkinson Foundation (Parkinsonfonden), and the Strategic Research Area at Lund University Multipark (multidisciplinary research in Parkinson's disease). Janelle Drouin-Ouellet is supported by a Canadian Institutes of Health Research (CIHR) fellowship (#358492), and Roger Barker is supported by an NIHR Biomedical Research Centre grant to the University of Cambridge/Addenbrooke's Hospital. Malin Parmar is a New York Stem Cell Foundation Robertson Investigator. Shelby Shrigley is funded by the European Union Horizon 2020 Programme (H2020-MSCA-ITN-2015) under the Marie Skłodowska-Curie Innovative Training Network and Grant Agreement No. 676408.

Direct neuronal reprogramming, by which a neuron is formed via direct conversion from a somatic cell without going through a pluripotent intermediate stage, allows for the possibility of generating patient-derived neurons. A unique feature of these so-called induced neurons (iNs) is the potential to maintain aging and epigenetic signatures of the donor, which is critical given that many diseases of the CNS are age related. Here, we review the published literature on the work that has been undertaken using iNs to model human brain disorders. Furthermore, as disease-modeling studies using this direct neuronal reprogramming approach are becoming more widely adopted, it is important to assess the criteria that are used to characterize the iNs, especially in relation to the extent to which they are mature adult neurons. In particular: i) what constitutes an iN cell, ii) which stages of conversion offer the earliest/optimal time to assess features that are specific to neurons and/or a disorder and iii) whether generating subtype-specific iNs is critical to the disease-related features that iNs express. Finally, we discuss the range of potential biomedical applications that can be explored using patient-specific models of neurological disorders with iNs, and the challenges that will need to be overcome in order to realize these applications. ; This research has received funding from the New York Stem Cell Foundation, the European Research Council under the European Union's Seventh Framework Programme: FP/2007-2013 Neuro Stem Cell Repair (no. 602278), ERC Grant Agreement no. 30971, the Swedish Research Council treatment of the future grant agreement K2012-99X-22324-01-5, the Swedish Research Council 70862601/Bagadilico, Swedish Parkinson Foundation (Parkinsonfonden), the Strategic Research Area at Lund University Multipark and StemTherapy. JJ is supported by the Swedish Foundation for Strategic Research (#FFL12-0074). JD is supported by a Canadian Institutes of Health Research (CIHR) fellowship (#358492), and RB is supported by an NIHR Biomedical Research Centre grant to the University of Cambridge/Addenbrooke's Hospital. MP is a New York Stem Cell Foundation—Robertson Investigator.