scholarly journals Xrp1 genetically interacts with the ALS-associated FUS orthologue caz and mediates its toxicity

2018 ◽  
Vol 217 (11) ◽  
pp. 3947-3964 ◽  
Author(s):  
Moushami Mallik ◽  
Marica Catinozzi ◽  
Clemens B. Hug ◽  
Li Zhang ◽  
Marina Wagner ◽  
...  
Keyword(s):  
Gene Expression ◽  
Life Span ◽  
Motor Neurons ◽  
Gene Expression Regulation ◽  
Genetic Interaction ◽  
Motor Deficits ◽  
Chromatin Binding ◽  
Mutant Phenotypes ◽  
Gene Expression Dysregulation ◽  
Lateral Sclerosis

Cabeza (caz) is the single Drosophila melanogaster orthologue of the human FET proteins FUS, TAF15, and EWSR1, which have been implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. In this study, we identified Xrp1, a nuclear chromatin-binding protein, as a key modifier of caz mutant phenotypes. Xrp1 expression was strongly up-regulated in caz mutants, and Xrp1 heterozygosity rescued their motor defects and life span. Interestingly, selective neuronal Xrp1 knockdown was sufficient to rescue, and neuronal Xrp1 overexpression phenocopied caz mutant phenotypes. The caz/Xrp1 genetic interaction depended on the functionality of the AT-hook DNA-binding domain in Xrp1, and the majority of Xrp1-interacting proteins are involved in gene expression regulation. Consistently, caz mutants displayed gene expression dysregulation, which was mitigated by Xrp1 heterozygosity. Finally, Xrp1 knockdown substantially rescued the motor deficits and life span of flies expressing ALS mutant FUS in motor neurons, implicating gene expression dysregulation in ALS-FUS pathogenesis.

scholarly journals A Complex Network of MicroRNAs Expressed in Brain and Genes Associated with Amyotrophic Lateral Sclerosis

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Santosh Shinde ◽  
Neelima Arora ◽  
Utpal Bhadra
Keyword(s):  
Gene Expression ◽  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Neurological Disease ◽  
Complex Interplay ◽  
Target Sites ◽  
Sites Of Action ◽  
Lateral Sclerosis ◽  
Similar Search

Amyotrophic Lateral Sclerosis (ALS) is a rare neurological disease affecting mainly motor neurons and often leads to paralysis and death in extreme cases. For exploring the role of microRNAs in genes regulation in ALS disease, miRanda was employed for prediction of target sites of miRNAs expressed in various parts of brain and CNS on 35 genes associated with ALS. Similar search was conducted using TargetScan and PicTar for prediction of target sites in3′UTR only. 1456 target sites were predicted using miRanda and more target sites were found in5′UTR and CDS region as compared to3′UTR. 11 target sites were predicted to be common by all the algorithms and, thus, these represent the most significant sites. Target site hotspots were identified and were recognized as hotspots for multiple miRNAs action, thus, acting as favoured sites of action for the repression of gene expression. The complex interplay of genes and miRNAs brought about by multiplicity and cooperativity was explored. This investigation will aid in elucidating the mechanism of action of miRNAs for the considered genes. The intrinsic network of miRNAs expressed in nervous system and genes associated with ALS may provide rapid and effective outcome for therapeutic applications and diagnosis.

scholarly journals SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export: genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Lydia M. Castelli ◽  
Luisa Cutillo ◽  
Cleide Dos Santos Souza ◽  
Alvaro Sanchez-Martinez ◽  
Ilaria Granata ◽  
...  
Keyword(s):  
Gene Expression ◽  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Nuclear Export ◽  
Gene Expression Signature ◽  
Critical Study ◽  
Genome Wide ◽  
Disease Modifying ◽  
Lateral Sclerosis ◽  
Partial Depletion

Abstract Background Loss of motor neurons in amyotrophic lateral sclerosis (ALS) leads to progressive paralysis and death. Dysregulation of thousands of RNA molecules with roles in multiple cellular pathways hinders the identification of ALS-causing alterations over downstream changes secondary to the neurodegenerative process. How many and which of these pathological gene expression changes require therapeutic normalisation remains a fundamental question. Methods Here, we investigated genome-wide RNA changes in C9ORF72-ALS patient-derived neurons and Drosophila, as well as upon neuroprotection taking advantage of our gene therapy approach which specifically inhibits the SRSF1-dependent nuclear export of pathological C9ORF72-repeat transcripts. This is a critical study to evaluate (i) the overall safety and efficacy of the partial depletion of SRSF1, a member of a protein family involved itself in gene expression, and (ii) a unique opportunity to identify neuroprotective RNA changes. Results Our study shows that manipulation of 362 transcripts out of 2257 pathological changes, in addition to inhibiting the nuclear export of repeat transcripts, is sufficient to confer neuroprotection in C9ORF72-ALS patient-derived neurons. In particular, expression of 90 disease-altered transcripts is fully reverted upon neuroprotection leading to the characterisation of a human C9ORF72-ALS disease-modifying gene expression signature. These findings were further investigated in vivo in diseased and neuroprotected Drosophila transcriptomes, highlighting a list of 21 neuroprotective changes conserved with 16 human orthologues in patient-derived neurons. We also functionally validated the high neuroprotective potential of one of these disease-modifying transcripts, demonstrating that inhibition of ALS-upregulated human KCNN1–3 (Drosophila SK) voltage-gated potassium channel orthologs mitigates degeneration of human motor neurons and Drosophila motor deficits. Conclusions Strikingly, the partial depletion of SRSF1 leads to expression changes in only a small proportion of disease-altered transcripts, indicating that not all RNA alterations need normalization and that the gene therapeutic approach is safe in the above preclinical models as it does not disrupt globally gene expression. The efficacy of this intervention is also validated at genome-wide level with transcripts modulated in the vast majority of biological processes affected in C9ORF72-ALS. Finally, the identification of a characteristic signature with key RNA changes modified in both the disease state and upon neuroprotection also provides potential new therapeutic targets and biomarkers.

scholarly journals TDP-43 proteinopathy alters the ribosome association of multiple mRNAs including the glypican Dally-like protein (Dlp)/GPC6

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Erik M. Lehmkuhl ◽  
Suvithanandhini Loganathan ◽  
Eric Alsop ◽  
Alexander D. Blythe ◽  
Tina Kovalik ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Rna Binding ◽  
Genetic Interaction ◽  
Neuromuscular Synapse ◽  
Pentose Phosphate ◽  
Interaction Data ◽  
Specific Effects ◽  
Genetic Interaction Data ◽  
Lateral Sclerosis ◽  
Ribosome Association

AbstractAmyotrophic lateral sclerosis (ALS) is a genetically heterogeneous neurodegenerative disease in which 97% of patients exhibit cytoplasmic aggregates containing the RNA binding protein TDP-43. Using tagged ribosome affinity purifications in Drosophila models of TDP-43 proteinopathy, we identified TDP-43 dependent translational alterations in motor neurons impacting the spliceosome, pentose phosphate and oxidative phosphorylation pathways. A subset of the mRNAs with altered ribosome association are also enriched in TDP-43 complexes suggesting that they may be direct targets. Among these, dlp mRNA, which encodes the glypican Dally like protein (Dlp)/GPC6, a wingless (Wg/Wnt) signaling regulator is insolubilized both in flies and patient tissues with TDP-43 pathology. While Dlp/GPC6 forms puncta in the Drosophila neuropil and ALS spinal cords, it is reduced at the neuromuscular synapse in flies suggesting compartment specific effects of TDP-43 proteinopathy. These findings together with genetic interaction data show that Dlp/GPC6 is a novel, physiologically relevant target of TDP-43 proteinopathy.

Gene expression profile of spinal motor neurons in sporadic amyotrophic lateral sclerosis

2005 ◽  
Vol 57 (2) ◽  
pp. 236-251 ◽  
Author(s):  
Yue-Mei Jiang ◽  
Masahiko Yamamoto ◽  
Yasushi Kobayashi ◽  
Tsuyoshi Yoshihara ◽  
Yideng Liang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Amyotrophic Lateral Sclerosis ◽  
Gene Expression Profile ◽  
Expression Profile ◽  
Motor Neurons ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Spinal Motor Neurons ◽  
Spinal Motor ◽  
Lateral Sclerosis

scholarly journals Integrative genetic analysis of the amyotrophic lateral sclerosis spinal cord implicates glial activation and suggests new risk genes

2021 ◽  
Author(s):  
Jack Humphrey ◽  
Sanan Venkatesh ◽  
Rahat Hasan ◽  
Jake T Herb ◽  
Katia de Paiva Lopes ◽  
...  
Keyword(s):  
Gene Expression ◽  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Cell Types ◽  
Lumbar Spinal Cord ◽  
Gene Expression Response ◽  
Expression Response ◽  
Lumbar Spinal ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressively fatal neurodegenerative disease affecting motor neurons in the brain and spinal cord. We used 380 post-mortem tissue RNA-seq transcriptomes from 154 ALS cases and 49 control individuals from cervical, thoracic, and lumbar spinal cord segments to investigate the gene expression response to ALS. We observed an increase in microglia and astrocyte expression, accompanied by a decrease in oligodendrocytes. By creating a gene co-expression network in the ALS samples, we identify several activated microglia modules that negatively correlate with retrospective disease duration. We map molecular quantitative trait loci and find several potential ALS risk loci that may act through gene expression or splicing in the spinal cord and assign putative cell-types for FNBP1, ACSL5, SH3RF1 and NFASC. Finally, we outline how repeat expansions that alter splicing of C9orf72 are tagged by common variants, and use this to suggest ATXN3 as a putative risk gene.

scholarly journals Multi-omic analysis of gametogenesis reveals a novel signature at the promoters and distal enhancers of active genes

2020 ◽  
Vol 48 (8) ◽  
pp. 4115-4138 ◽  
Author(s):  
Marion Crespo ◽  
Annelaure Damont ◽  
Melina Blanco ◽  
Emmanuelle Lastrucci ◽  
Sara El Kennani ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Expression Regulation ◽  
Regulation Of Gene Expression ◽  
Integrated Analysis ◽  
Chromatin Binding ◽  
Dynamic Modification ◽  
Transcription Regulators ◽  
Level Of Understanding ◽  
Chemical Groups ◽  
Active Genes

Abstract Epigenetic regulation of gene expression is tightly controlled by the dynamic modification of histones by chemical groups, the diversity of which has largely expanded over the past decade with the discovery of lysine acylations, catalyzed from acyl-coenzymes A. We investigated the dynamics of lysine acetylation and crotonylation on histones H3 and H4 during mouse spermatogenesis. Lysine crotonylation appeared to be of significant abundance compared to acetylation, particularly on Lys27 of histone H3 (H3K27cr) that accumulates in sperm in a cleaved form of H3. We identified the genomic localization of H3K27cr and studied its effects on transcription compared to the classical active mark H3K27ac at promoters and distal enhancers. The presence of both marks was strongly associated with highest gene expression. Assessment of their co-localization with transcription regulators (SLY, SOX30) and chromatin-binding proteins (BRD4, BRDT, BORIS and CTCF) indicated systematic highest binding when both active marks were present and different selective binding when present alone at chromatin. H3K27cr and H3K27ac finally mark the building of some sperm super-enhancers. This integrated analysis of omics data provides an unprecedented level of understanding of gene expression regulation by H3K27cr in comparison to H3K27ac, and reveals both synergistic and specific actions of each histone modification.

scholarly journals Loss of TDP-43 in astrocytes leads to motor deficits by triggering A1-like reactive phenotype and triglial dysfunction

2020 ◽  
Vol 117 (46) ◽  
pp. 29101-29112
Author(s):  
Audrey Yi Tyan Peng ◽  
Ira Agrawal ◽  
Wan Yun Ho ◽  
Yi-Chun Yen ◽  
Ashley J. Pinter ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Selective Reduction ◽  
Normal Function ◽  
Motor Deficits ◽  
Gfap Immunoreactivity ◽  
A Cell ◽  
Oligodendrocyte Precursor ◽  
Transcriptomic Level ◽  
Lateral Sclerosis

Patients with amyotrophic lateral sclerosis (ALS) can have abnormal TDP-43 aggregates in the nucleus and cytosol of their surviving neurons and glia. Although accumulating evidence indicates that astroglial dysfunction contributes to motor neuron degeneration in ALS, the normal function of TDP-43 in astrocytes are largely unknown, and the role of astroglial TDP-43 loss to ALS pathobiology remains to be clarified. Herein, we show that TDP-43–deleted astrocytes exhibit a cell-autonomous increase in GFAP immunoreactivity without affecting astrocyte or microglia proliferation. At the transcriptomic level, TDP-43–deleted astrocytes resemble A1-reactive astrocytes and induce microglia to increase C1q expression. These astrocytic changes do not cause loss of motor neurons in the spinal cord or denervation at the neuromuscular junction. In contrast, there is a selective reduction of mature oligodendrocytes, but not oligodendrocyte precursor cells, suggesting triglial dysfunction mediated by TDP-43 loss in astrocytes. Moreover, mice with astroglial TDP-43 deletion develop motor, but not sensory, deficits. Taken together, our results demonstrate that TDP-43 is required to maintain the protective functions of astrocytes relevant to the development of motor deficits in mice.

scholarly journals Safety and efficacy of C9ORF72-repeat RNA nuclear export inhibition in amyotrophic lateral sclerosis

2021 ◽  
Author(s):  
Lydia M Castelli ◽  
Luisa Cutillo ◽  
Cleide Dos Santos Souza ◽  
Alvaro Sanchez-Martinez ◽  
Ilaria Granata ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Therapy ◽  
Motor Neurons ◽  
Nuclear Export ◽  
Safety And Efficacy ◽  
Gene Therapy Approach ◽  
Genome Wide ◽  
Disease Modifying ◽  
Lateral Sclerosis ◽  
Partial Depletion

Background: Loss of motor neurons in amyotrophic lateral sclerosis (ALS) leads to progressive paralysis and death. Dysregulation of thousands of RNA molecules with roles in multiple cellular pathways hinders the identification of ALS-causing alterations over downstream changes secondary to the neurodegenerative process. How many and which of these pathological gene expression changes require therapeutic normalisation remains a fundamental question. Methods: Here, we investigated genome-wide RNA changes in C9ORF72-ALS patient-derived neurons and Drosophila, as well as upon neuroprotection taking advantage of our gene therapy approach which specifically inhibits the SRSF1-dependent nuclear export of pathological C9ORF72-repeat transcripts. This is a critical study to evaluate (i) the overall safety and efficacy of the partial depletion of SRSF1, a member of a protein family involved itself in gene expression, and (ii) a unique opportunity to identify neuroprotective RNA changes. Results: Our study demonstrates that manipulation of 362 transcripts out of 2,257 pathological changes in C9ORF72-ALS patient-derived neurons is sufficient to confer neuroprotection upon partial depletion of SRSF1. In particular, expression of 90 disease-altered transcripts is fully reverted upon neuroprotection leading to the characterisation of a human C9ORF72-ALS disease-modifying gene expression signature. These findings were further investigated in vivo in diseased and neuroprotected Drosophila transcriptomes, highlighting a list of 21 neuroprotective changes conserved with 16 human orthologues in patient-derived neurons. We also functionally validated the high therapeutic potential of one of these disease-modifying transcripts, demonstrating that inhibition of ALS-upregulated human KCNN1-3 (Drosophila SK) voltage-gated potassium channel orthologs mitigates degeneration of human motor neurons as well as Drosophila motor deficits. Conclusions: Strikingly, manipulating the expression levels of a small proportion of RNAs is sufficient to induce a therapeutic effect, further indicating that the SRSF1-targeted gene therapy approach is safe in the above preclinical models as it does not disrupt globally gene expression. The efficacy of this intervention is also validated at genome-wide level with therapeutically-induced RNA changes involved in the vast majority of biological processes affected in C9ORF72-ALS. Finally, the identification of a characteristic signature with key RNA changes modified in both the disease state and upon neuroprotection also provides potential new therapeutic targets and biomarkers.

scholarly journals TDP-43 proteinopathy alters the ribosome association of multiple mRNAs including the glypican Dally-like protein (Dlp)/GPC6

2020 ◽  
Author(s):  
Erik M Lehmkuhl ◽  
Suvithanandhini Loganathan ◽  
Eric Alsop ◽  
Alexander D Blythe ◽  
Tina Kovalik ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Rna Binding ◽  
Genetic Interaction ◽  
Neuromuscular Synapse ◽  
Pentose Phosphate ◽  
Interaction Data ◽  
Specific Effects ◽  
Genetic Interaction Data ◽  
Lateral Sclerosis ◽  
Ribosome Association

AbstractAmyotrophic lateral sclerosis (ALS) is a genetically heterogeneous neurodegenerative disease in which 97% of patients exhibit cytoplasmic aggregates containing the RNA binding protein TDP-43. Using tagged ribosome affinity purifications in Drosophila models of TDP-43 proteinopathy, we identified TDP-43 dependent translational alterations in motor neurons impacting the spliceosome, pentose phosphate and oxidative phosphorylation pathways. A subset of the mRNAs with altered ribosome association are also enriched in TDP-43 complexes suggesting that they may be direct targets. Among these, dlp mRNA, which encodes the glypican Dally like protein (Dlp)/GPC6, a wingless (Wg/Wnt) signaling regulator is insolubilized both in flies and patient tissues with TDP-43 pathology. While Dlp/GPC6 forms puncta in the Drosophila neuropil and ALS spinal cords, it is reduced at the neuromuscular synapse in flies suggesting compartment specific effects of TDP-43 proteinopathy. These findings together with genetic interaction data show that Dlp/GPC6 is a novel, physiologically relevant target of TDP-43 proteinopathy.

Sign in / Sign up

Export Citation Format

Share Document