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      BET bromodomain inhibitors PFI-1 and JQ1 are identified in an epigenetic compound screen to enhance C9ORF72 gene expression and shown to ameliorate C9ORF72-associated pathological and behavioral abnormalities in a C9ALS/FTD model

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          Abstract

          Background

          An intronic GGGGCC (G4C2) hexanucleotide repeat expansion (HRE) in the C9ORF72 gene is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), referred to as C9ALS/FTD. No cure or effective treatment exist for C9ALS/FTD. Three major molecular mechanisms have emerged to explain C9ALS/FTD disease mechanisms: (1) C9ORF72 loss-of-function through haploinsufficiency, (2) dipeptide repeat (DPR) proteins mediated toxicity by the translation of the repeat RNAs, and more controversial, (3) RNA-mediated toxicity by bidirectional transcription of the repeats that form intranuclear RNA foci. Recent studies indicate a double-hit pathogenic mechanism in C9ALS/FTD, where reduced C9ORF72 protein levels lead to impaired clearance of toxic DPRs. Here we explored whether pharmacological compounds can revert these pathological hallmarks in vitro and cognitive impairment in a C9ALS/FTD mouse model (C9BAC). We specifically focused our study on small molecule inhibitors targeting chromatin-regulating proteins (epidrugs) with the goal of increasing C9ORF72 gene expression and reduce toxic DPRs.

          Results

          We generated luciferase reporter cell lines containing 10 (control) or ≥ 90 (mutant) G4C2 HRE located between exon 1a and 1b of the human C9ORF72 gene. In a screen of 14 different epidrugs targeting bromodomains, chromodomains and histone-modifying enzymes, we found that several bromodomain and extra-terminal domain (BET) inhibitors (BETi), including PFI-1 and JQ1, increased luciferase reporter activity. Using primary cortical cultures from C9BAC mice, we further found that PFI-1 treatment increased the expression of V1-V3 transcripts of the human mutant C9ORF72 gene, reduced poly(GP)-DPR inclusions but enhanced intranuclear RNA foci. We also tested whether JQ1, an BETi previously shown to reach the mouse brain by intraperitoneal (i.p.) injection, can revert behavioral abnormalities in C9BAC mice. Interestingly, it was found that JQ1 administration (daily i.p. administration for 7 days) rescued hippocampal-dependent cognitive deficits in C9BAC mice.

          Conclusions

          Our findings place BET bromodomain inhibitors as a potential therapy for C9ALS/FTD by ameliorating C9ORF72-associated pathological and behavioral abnormalities. Our finding that PFI-1 increases accumulation of intranuclear RNA foci is in agreement with recent data in flies suggesting that nuclear RNA foci can be neuroprotective by sequestering repeat transcripts that result in toxic DPRs.

          Supplementary Information

          The online version contains supplementary material available at 10.1186/s13148-021-01039-z.

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          Most cited references 78

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          Double-slit photoelectron interference in strong-field ionization of the neon dimer

          Wave-particle duality is an inherent peculiarity of the quantum world. The double-slit experiment has been frequently used for understanding different aspects of this fundamental concept. The occurrence of interference rests on the lack of which-way information and on the absence of decoherence mechanisms, which could scramble the wave fronts. Here, we report on the observation of two-center interference in the molecular-frame photoelectron momentum distribution upon ionization of the neon dimer by a strong laser field. Postselection of ions, which are measured in coincidence with electrons, allows choosing the symmetry of the residual ion, leading to observation of both, gerade and ungerade, types of interference.
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            Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.

            Ubiquitin-positive, tau- and alpha-synuclein-negative inclusions are hallmarks of frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis. Although the identity of the ubiquitinated protein specific to either disorder was unknown, we showed that TDP-43 is the major disease protein in both disorders. Pathologic TDP-43 was hyper-phosphorylated, ubiquitinated, and cleaved to generate C-terminal fragments and was recovered only from affected central nervous system regions, including hippocampus, neocortex, and spinal cord. TDP-43 represents the common pathologic substrate linking these neurodegenerative disorders.
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              Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS.

              Several families have been reported with autosomal-dominant frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), genetically linked to chromosome 9p21. Here, we report an expansion of a noncoding GGGGCC hexanucleotide repeat in the gene C9ORF72 that is strongly associated with disease in a large FTD/ALS kindred, previously reported to be conclusively linked to chromosome 9p. This same repeat expansion was identified in the majority of our families with a combined FTD/ALS phenotype and TDP-43-based pathology. Analysis of extended clinical series found the C9ORF72 repeat expansion to be the most common genetic abnormality in both familial FTD (11.7%) and familial ALS (23.5%). The repeat expansion leads to the loss of one alternatively spliced C9ORF72 transcript and to formation of nuclear RNA foci, suggesting multiple disease mechanisms. Our findings indicate that repeat expansion in C9ORF72 is a major cause of both FTD and ALS. Copyright © 2011 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                mmontecino@unab.cl
                bvanzundert@unab.cl
                Journal
                Clin Epigenetics
                Clin Epigenetics
                Clinical Epigenetics
                BioMed Central (London )
                1868-7075
                1868-7083
                16 March 2021
                16 March 2021
                2021
                : 13
                Affiliations
                [1 ]GRID grid.412848.3, ISNI 0000 0001 2156 804X, Institute of Biomedical Sciences (ICB), Faculty of Medicine & Faculty of Life Sciences, , Universidad Andres Bello, ; Santiago, Chile
                [2 ]GRID grid.168645.8, ISNI 0000 0001 0742 0364, Department of Neurology, , University of Massachusetts Medical School (UMMS), ; Worcester, MA USA
                [3 ]FONDAP Center for Genome Regulation, Santiago, Chile
                [4 ]GRID grid.7870.8, ISNI 0000 0001 2157 0406, CARE Biomedical Research Center, Faculty of Biological Sciences, , Pontificia Universidad Católica de Chile, ; Santiago, Chile
                Article
                1039
                10.1186/s13148-021-01039-z
                7962347
                © The Author(s) 2021

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100006402, ALS Therapy Alliance;
                Award ID: ATA-2014-F-034
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000971, Amyotrophic Lateral Sclerosis Association;
                Award ID: 20-DDC-497
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100014012, FightMND;
                Funded by: CONICYT PIA/BASAL
                Award ID: AFB 170005 CARE UC
                Award Recipient :
                Funded by: DRI-USA
                Award ID: 2013-0030
                Award Recipient :
                Funded by: FONDECYT
                Award ID: 1181645
                Award Recipient :
                Funded by: FONDAP
                Award ID: 15090007
                Award Recipient :
                Funded by: FONDECYT
                Award ID: 1170878
                Award Recipient :
                Funded by: CONICYT
                Award ID: 201161486
                Award Recipient :
                Funded by: ALS-One
                Funded by: ALS-FindingACure
                Funded by: the Angel Fund for ALS Research
                Funded by: the Cellucci Fund for ALS Research
                Funded by: the Michael Rosenfeld Fund
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: NS111990-01
                Award ID: R01 NS104022
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2021

                Genetics

                c9orf72, epigenetics, bet inhibitors, dpr, rna foci, memory

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