scholarly journals Early epigenomic and transcriptional changes reveal Elk-1 transcription factor as a therapeutic target in Huntington’s disease

2019 ◽  
Vol 116 (49) ◽  
pp. 24840-24851 ◽  
Author(s):  
Ferah Yildirim ◽  
Christopher W. Ng ◽  
Vincent Kappes ◽  
Tobias Ehrenberger ◽  
Siobhan K. Rigby ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Disease Onset ◽  
Beneficial Effects ◽  
Transcriptional Dysregulation ◽  
Clinical Onset ◽  
Transcriptional Changes ◽  
Chromatin Profiling

Huntington’s disease (HD) is a chronic neurodegenerative disorder characterized by a late clinical onset despite ubiquitous expression of the mutant Huntingtin gene (HTT) from birth. Transcriptional dysregulation is a pivotal feature of HD. Yet, the genes that are altered in the prodromal period and their regulators, which present opportunities for therapeutic intervention, remain to be elucidated. Using transcriptional and chromatin profiling, we found aberrant transcription and changes in histone H3K27acetylation in the striatum of R6/1 mice during the presymptomatic disease stages. Integrating these data, we identified the Elk-1 transcription factor as a candidate regulator of prodromal changes in HD. Exogenous expression of Elk-1 exerted beneficial effects in a primary striatal cell culture model of HD, and adeno-associated virus-mediated Elk-1 overexpression alleviated transcriptional dysregulation in R6/1 mice. Collectively, our work demonstrates that aberrant gene expression precedes overt disease onset in HD, identifies the Elk-1 transcription factor as a key regulator linked to early epigenetic and transcriptional changes in HD, and presents evidence for Elk-1 as a target for alleviating molecular pathology in HD.

scholarly journals Bioinformatic gene analysis for potential therapeutic targets of Huntington’s disease in pre-symptomatic and symptomatic stage

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Chunchen Xiang ◽  
Shengri Cong ◽  
Bin Liang ◽  
Shuyan Cong
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Differentially Expressed Genes ◽  
Bioinformatics Analysis ◽  
Neurodegenerative Disorder ◽  
Psychiatric Symptoms ◽  
Therapeutic Targets ◽  
Differentially Expressed ◽  
Hub Genes ◽  
Transcriptional Dysregulation

Abstract Background Huntington’s disease (HD) is a neurodegenerative disorder characterized by psychiatric symptoms, serious motor and cognitive deficits. Certain pathological changes can already be observed in pre-symptomatic HD (pre-HD) patients; however, the underlying molecular pathogenesis is still uncertain and no effective treatments are available until now. Here, we reanalyzed HD-related differentially expressed genes from the GEO database between symptomatic HD patients, pre-HD individuals, and healthy controls using bioinformatics analysis, hoping to get more insight in the pathogenesis of both pre-HD and HD, and shed a light in the potential therapeutic targets of the disease. Methods Pre-HD and symptomatic HD differentially expressed genes (DEGs) were screened by bioinformatics analysis Gene Expression Omnibus (GEO) dataset GSE1751. A protein–protein interaction (PPI) network was used to select hub genes. Subsequently, Gene Ontology (GO) enrichment analysis of DEGs and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of hub genes were applied. Dataset GSE24250 was downloaded to verify our hub genes by the Kaplan–Meier method using Graphpad Prism 5.0. Finally, target miRNAs of intersected hub genes involved in pre-HD and symptomatic HD were predicted. Results A total of 37 and 985 DEGs were identified in pre-HD and symptomatic HD, respectively. The hub genes, SIRT1, SUZ12, and PSMC6, may be implicated in pre-HD, and the hub genes, FIS1, SIRT1, CCNH, SUZ12, and 10 others, may be implicated in symptomatic HD. The intersected hub genes, SIRT1 and SUZ12, and their predicted target miRNAs, in particular miR-22-3p and miR-19b, may be significantly associated with pre-HD. Conclusion The PSMC6, SIRT1, and SUZ12 genes and their related ubiquitin-mediated proteolysis, transcriptional dysregulation, and histone metabolism are significantly associated with pre-HD. FIS1, CCNH, and their related mitochondrial disruption and transcriptional dysregulation processes are related to symptomatic HD, which might shed a light on the elucidation of potential therapeutic targets in HD.

scholarly journals Laser Evoked Potentials in Early and Presymptomatic Huntington’s Disease

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Marina de Tommaso ◽  
Giovanni Franco ◽  
Katia Ricci ◽  
Anna Montemurno ◽  
Vittorio Sciruicchio
Keyword(s):  
Evoked Potentials ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Functional Decline ◽  
Disease Onset ◽  
Laser Evoked Potentials ◽  
Clinical Onset ◽  
Pain Pathways ◽  
Potential Biomarker ◽  
Pain Symptoms

Pain was rarely studied in Huntington’s disease (HD). We presently aimed to extend our previous study on pain pathways functions by laser evoked potentials (LEPs) to a larger cohort of early unmedicated HD patients and a small group of presymptomatic HD (PHD) subjects. Forty-two early HD patients, 10 PHD patients, and 64 controls were submitted to LEPs by right-hand stimulation. Two series of 30 laser stimuli were delivered, and artifact-free responses were averaged. The N1, N2, and P2 latencies were significantly increased and the N2P2 amplitude significantly reduced in HD patients compared to controls. In the HD group, the LEPs abnormalities correlated with functional decline. PHD subjects showed a slight and insignificant increase in LEPs latencies, which was inversely correlated with the possible age of HD clinical onset. Data of the present study seem to suggest that the functional state of nociceptive pathways as assessed by LEPs may be a potential biomarker of disease onset and progression. The assessment of pain symptoms in premanifest and manifest HD may also open a new scenario in terms of subtle disturbances of pain processing, which may have a role in the global burden of the disease.

scholarly journals Single-nucleus RNA-seq reveals dysregulation of striatal cell identity due to Huntington’s disease mutations

2020 ◽  
Author(s):  
Sonia Malaiya ◽  
Marcia Cortes-Gutierrez ◽  
Brian R. Herb ◽  
Sydney R. Coffey ◽  
Samuel R.W. Legg ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Cell Types ◽  
Transcriptional Networks ◽  
Rna Seq ◽  
Cell Type ◽  
Cell Identity ◽  
Transcriptional Changes ◽  
Cell Type Specific

ABSTRACTHuntington’s disease (HD) is a dominantly inherited neurodegenerative disorder caused by a trinucleotide expansion in exon 1 of the huntingtin (Htt) gene. Cell death in HD occurs primarily in striatal medium spiny neurons (MSNs), but the involvement of specific MSN subtypes and of other striatal cell types remains poorly understood. To gain insight into cell type-specific disease processes, we studied the nuclear transcriptomes of 4,524 cells from the striatum of a genetically precise knock-in mouse model of the HD mutation, HttQ175/+, and from wildtype controls. We used 14-15-month-old mice, a time point roughly equivalent to an early stage of symptomatic human disease. Cell type distributions indicated selective loss of D2 MSNs and increased microglia in aged HttQ175/+ mice. Thousands of differentially expressed genes were distributed across most striatal cell types, including transcriptional changes in glial populations that are not apparent from RNA-seq of bulk tissue. Reconstruction of cell typespecific transcriptional networks revealed a striking pattern of bidirectional dysregulation for many cell type-specific genes. Typically, these genes were repressed in their primary cell type, yet de-repressed in other striatal cell types. Integration with existing epigenomic and transcriptomic data suggest that partial loss-of-function of the Polycomb Repressive Complex 2 (PRC2) may underlie many of these transcriptional changes, leading to deficits in the maintenance of cell identity across virtually all cell types in the adult striatum.

scholarly journals A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington's disease

2008 ◽  
Vol 205 (8) ◽  
pp. 1869-1877 ◽  
Author(s):  
Maria Björkqvist ◽  
Edward J. Wild ◽  
Jenny Thiele ◽  
Aurelio Silvestroni ◽  
Ralph Andre ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Immune Activation ◽  
Clinical Symptoms ◽  
Neurodegenerative Disorder ◽  
Innate Immune ◽  
Brain Pathology ◽  
Clinical Onset ◽  
Gene Carriers ◽  
A Cell

Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by both neurological and systemic abnormalities. We examined the peripheral immune system and found widespread evidence of innate immune activation detectable in plasma throughout the course of HD. Interleukin 6 levels were increased in HD gene carriers with a mean of 16 years before the predicted onset of clinical symptoms. To our knowledge, this is the earliest plasma abnormality identified in HD. Monocytes from HD subjects expressed mutant huntingtin and were pathologically hyperactive in response to stimulation, suggesting that the mutant protein triggers a cell-autonomous immune activation. A similar pattern was seen in macrophages and microglia from HD mouse models, and the cerebrospinal fluid and striatum of HD patients exhibited abnormal immune activation, suggesting that immune dysfunction plays a role in brain pathology. Collectively, our data suggest parallel central nervous system and peripheral pathogenic pathways of immune activation in HD.

Transcriptional dysregulation of coding and non-coding genes in cellular models of Huntington's disease

2009 ◽  
Vol 37 (6) ◽  
pp. 1270-1275 ◽  
Author(s):  
Angela Bithell ◽  
Rory Johnson ◽  
Noel J. Buckley
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Target Genes ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Cag Repeat ◽  
Contributory Factor ◽  
Cellular Models

HD (Huntington's disease) is a late onset heritable neurodegenerative disorder that is characterized by neuronal dysfunction and death, particularly in the cerebral cortex and medium spiny neurons of the striatum. This is followed by progressive chorea, dementia and emotional dysfunction, eventually resulting in death. HD is caused by an expanded CAG repeat in the first exon of the HD gene that results in an abnormally elongated polyQ (polyglutamine) tract in its protein product, Htt (Huntingtin). Wild-type Htt is largely cytoplasmic; however, in HD, proteolytic N-terminal fragments of Htt form insoluble deposits in both the cytoplasm and nucleus, provoking the idea that mutHtt (mutant Htt) causes transcriptional dysfunction. While a number of specific transcription factors and co-factors have been proposed as mediators of mutHtt toxicity, the causal relationship between these Htt/transcription factor interactions and HD pathology remains unknown. Previous work has highlighted REST [RE1 (repressor element 1)-silencing transcription factor] as one such transcription factor. REST is a master regulator of neuronal genes, repressing their expression. Many of its direct target genes are known or suspected to have a role in HD pathogenesis, including BDNF (brain-derived neurotrophic factor). Recent evidence has also shown that REST regulates transcription of regulatory miRNAs (microRNAs), many of which are known to regulate neuronal gene expression and are dysregulated in HD. Thus repression of miRNAs constitutes a second, indirect mechanism by which REST can alter the neuronal transcriptome in HD. We will describe the evidence that disruption to the REST regulon brought about by a loss of interaction between REST and mutHtt may be a key contributory factor in the widespread dysregulation of gene expression in HD.

Transcriptional dysregulation in Huntington’s Disease. The role in pathogenesis and potency for pharmacological targeting.

2020 ◽  
Vol 27 ◽  
Author(s):  
Aleksandra Pogoda ◽  
Natalia Chmielewska ◽  
Piotr Maciejak ◽  
Janusz Szyndler
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Regulatory Protein ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Molecular Manipulation

: Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by a mutation in the gene that encodes a critical cell regulatory protein, huntingtin (Htt). The expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats causes improper folding of functional proteins and is an initial trigger of pathological changes in the brain. Recent research has indicated that the functional dysregulation of many transcription factors underlies the neurodegenerative processes that accompany HD. These disturbances are caused not only by the loss of wild-type Htt (WT Htt) function but also by the occurrence of abnormalities that result from the action of mutant Htt (mHtt). In this review, we aim to describe the role of transcription factors that are currently thought to be strongly associated with HD pathogenesis, namely, RE1-silencing transcription factor, also known as neuron-restrictive silencer factor (REST/NRSF), forkhead box proteins (FOXPs), peroxisome proliferator-activated receptor gamma coactivator-1a (PGC1α), heat shock transcription factor 1 (HSF1), and nuclear factor κ light-chain-enhancer of activated B cells (NF-κB). We also take into account the role of these factors in the phenotype of HD as well as potential pharmacological interventions targeting the analyzed proteins. Furthermore, we considered whether molecular manipulation resulting in changes in transcription factor function may have clinical potency for treating HD.

scholarly journals Genetic deletion of S6k1 does not rescue the phenotypic deficits observed in the R6/2 mouse model of Huntington’s disease

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Elaine E. Irvine ◽  
Loukia Katsouri ◽  
Florian Plattner ◽  
Hind Al-Qassab ◽  
Rand Al-Nackkash ◽  
...  
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Mammalian Target Of Rapamycin ◽  
Protein Aggregate ◽  
Beneficial Effects ◽  
Age Related ◽  
Signalling Molecule ◽  
Mutant Huntingtin Protein

Abstract Huntington’s disease (HD) is a fatal inherited autosomal dominant neurodegenerative disorder caused by an expansion in the number of CAG trinucleotide repeats in the huntingtin gene. The disease is characterized by motor, behavioural and cognitive symptoms for which at present there are no disease altering treatments. It has been shown that manipulating the mTOR (mammalian target of rapamycin) pathway using rapamycin or its analogue CCI-779 can improve the cellular and behavioural phenotypes of HD models. Ribosomal protein S6 kinase 1 (S6K1) is a major downstream signalling molecule of mTOR, and its activity is reduced by rapamycin suggesting that deregulation of S6K1 activity may be beneficial in HD. Furthermore, S6k1 knockout mice have increased lifespan and improvement in age-related phenotypes. To evalute the potential benefit of S6k1 loss on HD-related phenotypes, we crossed the R6/2 HD model with the long-lived S6k1 knockout mouse line. We found that S6k1 knockout does not ameliorate behavioural or physiological phenotypes in the R6/2 mouse model. Additionally, no improvements were seen in brain mass reduction or mutant huntingtin protein aggregate levels. Therefore, these results suggest that while a reduction in S6K1 signalling has beneficial effects on ageing it is unlikely to be a therapeutic strategy for HD patients.

scholarly journals Neuroimaging, Urinary, and Plasma Biomarkers of Treatment Response in Huntington’s Disease: Preclinical Evidence with the p75NTR Ligand LM11A-31

2021 ◽  
Author(s):  
Danielle A. Simmons ◽  
Brian D. Mills ◽  
Robert R. Butler III ◽  
Jason Kuan ◽  
Tyne L. M. McHugh ◽  
...  
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Treatment Response ◽  
Diffusion Tensor ◽  
Disease Onset ◽  
Therapeutic Effects ◽  
Plasma Cytokine ◽  
Cytokine Levels ◽  
Pharmacodynamic Biomarkers

AbstractHuntington’s disease (HD) is caused by an expansion of the CAG repeat in the huntingtin gene leading to preferential neurodegeneration of the striatum. Disease-modifying treatments are not yet available to HD patients and their development would be facilitated by translatable pharmacodynamic biomarkers. Multi-modal magnetic resonance imaging (MRI) and plasma cytokines have been suggested as disease onset/progression biomarkers, but their ability to detect treatment efficacy is understudied. This study used the R6/2 mouse model of HD to assess if structural neuroimaging and biofluid assays can detect treatment response using as a prototype the small molecule p75NTR ligand LM11A-31, shown previously to reduce HD phenotypes in these mice. LM11A-31 alleviated volume reductions in multiple brain regions, including striatum, of vehicle-treated R6/2 mice relative to wild-types (WTs), as assessed with in vivo MRI. LM11A-31 also normalized changes in diffusion tensor imaging (DTI) metrics and diminished increases in certain plasma cytokine levels, including tumor necrosis factor-alpha and interleukin-6, in R6/2 mice. Finally, R6/2-vehicle mice had increased urinary levels of the p75NTR extracellular domain (ecd), a cleavage product released with pro-apoptotic ligand binding that detects the progression of other neurodegenerative diseases; LM11A-31 reduced this increase. These results are the first to show that urinary p75NTR-ecd levels are elevated in an HD mouse model and can be used to detect therapeutic effects. These data also indicate that multi-modal MRI and plasma cytokine levels may be effective pharmacodynamic biomarkers and that using combinations of these markers would be a viable and powerful option for clinical trials.

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