| 1. |
- Pircs, Karolina, et al.
(author)
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Huntingtin Aggregation Impairs Autophagy, Leading to Argonaute-2 Accumulation and Global MicroRNA Dysregulation
- 2018
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In: Cell Reports. - : Elsevier BV. - 2211-1247. ; 24:6, s. 1397-1406
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Journal article (peer-reviewed)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.
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| 2. |
- Abbasi, Rasha, et al.
(author)
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IceCube search for neutrinos from GRB 221009A
- 2023
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In: Proceedings of 38th International Cosmic Ray Conference (ICRC 2023). - : Sissa Medialab Srl.
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Conference paper (peer-reviewed)abstract
- GRB 221009A is the brightest Gamma Ray Burst (GRB) ever observed. The observed extremelyhigh flux of high and very-high-energy photons provide a unique opportunity to probe the predictedneutrino counterpart to the electromagnetic emission. We have used a variety of methods to searchfor neutrinos in coincidence with the GRB over several time windows during the precursor, promptand afterglow phases of the GRB. MeV scale neutrinos are studied using photo-multiplier ratescalers which are normally used to search for galactic core-collapse supernovae neutrinos. GeVneutrinos are searched starting with DeepCore triggers. These events don’t have directionallocalization, but instead can indicate an excess in the rate of events. 10 GeV - 1 TeV and >TeVneutrinos are searched using traditional neutrino point source methods which take into accountthe direction and time of events with DeepCore and the entire IceCube detector respectively. The>TeV results include both a fast-response analysis conducted by IceCube in real-time with timewindows of T0 − 1 to T0 + 2 hours and T0 ± 1 day around the time of GRB 221009A, as well asan offline analysis with 3 new time windows up to a time window of T0 − 1 to T0 + 14 days, thelongest time period we consider. The combination of observations by IceCube covers 9 ordersof magnitude in neutrino energy, from MeV to PeV, placing upper limits across the range forpredicted neutrino emission.
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| 3. |
- Brattås, Per Ludvik, et al.
(author)
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Impact of differential and time-dependent autophagy activation on therapeutic efficacy in a model of Huntington disease
- 2021
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In: Autophagy. - : Informa UK Limited. - 1554-8627 .- 1554-8635. ; 17:6, s. 1316-1329
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Journal article (peer-reviewed)abstract
- Activation of macroautophagy/autophagy, a key mechanism involved in the degradation and removal of aggregated proteins, can successfully reverse Huntington disease phenotypes in various model systems. How neuronal autophagy impairments need to be considered in Huntington disease progression to achieve a therapeutic effect is currently not known. In this study, we used a mouse model of HTT (huntingtin) protein aggregation to investigate how different methods and timing of autophagy activation influence the efficacy of autophagy-activating treatment in vivo. We found that overexpression of human TFEB, a master regulator of autophagy, did not decrease mutant HTT aggregation. On the other hand, Becn1 overexpression, an autophagic regulator that plays a key role in autophagosome formation, partially cleared mutant HTT aggregates and restored neuronal pathology, but only when administered early in the disease progression. When Becn1 was administered at a later stage, when prominent mutant HTT accumulation and autophagy impairments have occurred, Becn1 overexpression did not rescue the mutant HTT-associated phenotypes. Together, these results demonstrate that the targets used to activate autophagy, as well as the timing of autophagy activation, are crucial for achieving efficient therapeutic effects.
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| 4. |
- Campbell, PJ, et al.
(author)
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Pan-cancer analysis of whole genomes
- 2020
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In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
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Journal article (peer-reviewed)abstract
- Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1–3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10–18.
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| 5. |
- Jönsson, Marie E, et al.
(author)
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Activation of endogenous retroviruses during brain development causes an inflammatory response
- 2021
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In: EMBO Journal. - : EMBO Press. - 0261-4189 .- 1460-2075. ; 40:9
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Journal article (peer-reviewed)abstract
- Endogenous retroviruses (ERVs) make up a large fraction of mammalian genomes and are thought to contribute to human disease, including brain disorders. In the brain, aberrant activation of ERVs is a potential trigger for an inflammatory response, but mechanistic insight into this phenomenon remains lacking. Using CRISPR/Cas9-based gene disruption of the epigenetic co-repressor protein Trim28, we found a dynamic H3K9me3-dependent regulation of ERVs in proliferating neural progenitor cells (NPCs), but not in adult neurons. In vivo deletion of Trim28 in cortical NPCs during mouse brain development resulted in viable offspring expressing high levels of ERVs in excitatory neurons in the adult brain. Neuronal ERV expression was linked to activated microglia and the presence of ERV-derived proteins in aggregate-like structures. This study demonstrates that brain development is a critical period for the silencing of ERVs and provides causal in vivo evidence demonstrating that transcriptional activation of ERV in neurons results in an inflammatory response.
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| 6. |
- Jönsson, Marie E., et al.
(author)
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Activation of neuronal genes via LINE-1 elements upon global DNA demethylation in human neural progenitors
- 2019
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1
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Journal article (peer-reviewed)abstract
- DNA methylation contributes to the maintenance of genomic integrity in somatic cells, in part through the silencing of transposable elements. In this study, we use CRISPR-Cas9 technology to delete DNMT1, the DNA methyltransferase key for DNA methylation maintenance, in human neural progenitor cells (hNPCs). We observe that inactivation of DNMT1 in hNPCs results in viable, proliferating cells despite a global loss of DNA CpG-methylation. DNA demethylation leads to specific transcriptional activation and chromatin remodeling of evolutionarily young, hominoid-specific LINE-1 elements (L1s), while older L1s and other classes of transposable elements remain silent. The activated L1s act as alternative promoters for many protein-coding genes involved in neuronal functions, revealing a hominoid-specific L1-based transcriptional network controlled by DNA methylation that influences neuronal protein-coding genes. Our results provide mechanistic insight into the role of DNA methylation in silencing transposable elements in somatic human cells, as well as further implicating L1s in human brain development and disease.
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| 7. |
- Madsen, Signe Sloth, et al.
(author)
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Neuroplasticity induced by general anaesthesia : study protocol for a randomised cross-over clinical trial exploring the effects of sevoflurane and propofol on the brain - A 3-T magnetic resonance imaging study of healthy volunteers
- 2020
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In: Trials. - : Springer Science and Business Media LLC. - 1745-6215. ; 21:1
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Journal article (peer-reviewed)abstract
- Background: Although used extensively worldwide, the effects of general anaesthesia on the human brain remain largely elusive. Moreover, general anaesthesia may contribute to serious conditions or adverse events such as postoperative cognitive dysfunction and delirium. To understand the basic mechanisms of general anaesthesia, this project aims to study and compare possible de novo neuroplastic changes induced by two commonly used types of general anaesthesia, i.e. inhalation anaesthesia by sevoflurane and intravenously administered anaesthesia by propofol. In addition, we wish to to explore possible associations between neuroplastic changes, neuropsychological adverse effects and subjective changes in fatigue and well-being. Methods: This is a randomised, participant- and assessor-blinded, cross-over clinical trial. Thirty healthy volunteers (male:female ratio 1:1) will be randomised to general anaesthesia by either sevoflurane or propofol. Multimodal magnetic resonance imaging (MRI) of the brain will be performed before and after general anaesthesia and repeated after 1 and 8 days. Each magnetic resonance imaging session will be accompanied by cognitive testing and questionnaires on fatigue and well-being. After a wash-out period of 4 weeks, the volunteers will receive the other type of anaesthetic (sevoflurane or propofol), followed by the same series of tests. Primary outcomes: changes in T1-weighted 3D anatomy and diffusion tensor imaging. Secondary outcomes: changes in resting-state functional magnetic resonance imaging, fatigue, well-being, cognitive function, correlations between magnetic resonance imaging findings and the clinical outcomes (questionnaires and cognitive function). Exploratory outcomes: changes in cerebral perfusion and oxygen metabolism, lactate, and response to visual stimuli. Discussion: To the best of our knowledge, this is the most extensive and advanced series of studies with head-to-head comparison of two widely used methods for general anaesthesia. Recruitment was initiated in September 2019. Trial registration: Approved by the Research Ethics Committee in the Capital Region of Denmark, ref. H-18028925 (6 September 2018). EudraCT and Danish Medicines Agency: 2018-001252-35 (23 March 2018). www.clinicaltrials.gov, ID: NCT04125121. Retrospectively registered on 10 October 2019.
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