scholarly journals Heat Shock Factor 1 Directly Regulates Postsynaptic Scaffolding PSD-95 in Aging and Huntington’s Disease and Influences Striatal Synaptic Density

2021 ◽  
Vol 22 (23) ◽  
pp. 13113
Author(s):  
Nicole Zarate ◽  
Taylor A. Intihar ◽  
Dahyun Yu ◽  
Jacob Sawyer ◽  
Wei Tsai ◽  
...  
Keyword(s):  
Heat Shock ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Regulatory Elements ◽  
Scaffolding Protein ◽  
Heat Shock Factor 1 ◽  
Dependent Manner ◽  
Regulatory Relationship ◽  
Direct Role ◽  
Protein Levels

PSD-95 (Dlg4) is an ionotropic glutamate receptor scaffolding protein essential in synapse stability and neurotransmission. PSD-95 levels are reduced during aging and in neurodegenerative diseases like Huntington’s disease (HD), and it is believed to contribute to synaptic dysfunction and behavioral deficits. However, the mechanism responsible for PSD-95 dysregulation under these conditions is unknown. The Heat Shock transcription Factor 1 (HSF1), canonically known for its role in protein homeostasis, is also depleted in both aging and HD. Synaptic protein levels, including PSD-95, are influenced by alterations in HSF1 levels and activity, but the direct regulatory relationship between PSD-95 and HSF1 has yet to be determined. Here, we showed that HSF1 chronic or acute reduction in cell lines and mice decreased PSD-95 expression. Furthermore, Hsf1(+/−) mice had reduced PSD-95 synaptic puncta that paralleled a loss in thalamo-striatal excitatory synapses, an important circuit disrupted early in HD. We demonstrated that HSF1 binds to regulatory elements present in the PSD-95 gene and directly regulates PSD-95 expression. HSF1 DNA-binding on the PSD-95 gene was disrupted in an age-dependent manner in WT mice and worsened in HD cells and mice, leading to reduced PSD-95 levels. These results demonstrate a direct role of HSF1 in synaptic gene regulation that has important implications in synapse maintenance in basal and pathological conditions.

scholarly journals Heat Shock Factor 1 Directly Regulates Postsynaptic Scaffolding PSD-95 in Aging and Huntington’s Disease and Influences Striatal Synaptic Density

2021 ◽  
Author(s):  
Nicole Zarate ◽  
Taylor A Intihar ◽  
Dahyun Yu ◽  
Jacob Sawyer ◽  
Wei Tsai ◽  
...  
Keyword(s):  
Heat Shock ◽  
Regulatory Elements ◽  
Scaffolding Protein ◽  
Excitatory Synapses ◽  
Heat Shock Factor 1 ◽  
Dependent Manner ◽  
Regulatory Relationship ◽  
Direct Role ◽  
Protein Levels ◽  
Synapse Maintenance

PSD-95 (Dlg4) is an ionotropic glutamate receptor scaffolding protein essential in synapse stability and neurotransmission. PSD-95 levels are reduced during aging and in neurodegenerative diseases like Huntington’s disease (HD), and it is believed to contribute to synaptic dysfunction and behavioral deficits. However, the mechanism responsible for PSD-95 dysregulation under these conditions is unknown. The Heat Shock transcription Factor 1 (HSF1), canonically known for its role in protein homeostasis, is also depleted in both aging and HD. Synaptic protein levels, including PSD-95, are influenced by alterations in HSF1 levels and activity, but the direct regulatory relationship between PSD-95 and HSF1 has yet to be determined. Here, we showed that HSF1 chronic or acute depletion in cell lines and mice decreased PSD-95 expression. Furthermore, HSF1(+/-) mice had reduced PSD-95 synaptic puncta that paralleled a loss in thalamo-striatal excitatory synapses, an important circuit disrupted early in HD. We demonstrated that HSF1 binds to regulatory elements present in the PSD-95 gene and directly regulates PSD-95 expression. HSF1 DNA-binding on the PSD-95 gene was disrupted in an age-dependent manner in WT mice and worsened in HD cells and mice, leading to reduced PSD-95 levels. These results demonstrate a direct role of HSF1 in synaptic gene regulation that has important implications in synapse maintenance in basal and pathological conditions.

scholarly journals HSF1-dependent and -independent regulation of the mammalian in vivo heat shock response and its impairment in Huntington's disease mouse models

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Andreas Neueder ◽  
Theresa A. Gipson ◽  
Sophie Batterton ◽  
Hayley J. Lazell ◽  
Pamela P. Farshim ◽  
...  
Keyword(s):  
Heat Shock ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mouse Models ◽  
Heat Shock Response ◽  
Shock Response

Hypothesis: huntingtin may function in membrane association and vesicular traffickingThis paper is one of a selection of papers published in this Special Issue, entitled CSBMCB — Membrane Proteins in Health and Disease.

2006 ◽  
Vol 84 (6) ◽  
pp. 912-917 ◽  
Author(s):  
Ray Truant ◽  
Randy Atwal ◽  
Anjee Burtnik
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Protein Interactions ◽  
Cell Biology ◽  
Genetic Disorder ◽  
Scaffolding Protein ◽  
Membrane Association ◽  
Protein Protein Interactions ◽  
Polyglutamine Expansion ◽  
Exact Function

Huntington’s disease is a progressive neurodegenerative genetic disorder that is caused by a CAG triplet-repeat expansion in the first exon of the IT15 gene. This CAG expansion results in polyglutamine expansion in the 350 kDa huntingtin protein. The exact function of huntingtin is unknown. Understanding the pathological triggers of mutant huntingtin, and distinguishing the cause of disease from downstream effects, is critical to designing therapeutic strategies and defining long- and short-term goals of therapy. Many studies that have sought to determine the functions of huntingtin by determining huntingtin’s protein–protein interactions have been published. Through these studies, huntingtin has been seen to interact with a large number of proteins, and is likely a scaffolding protein for protein–protein interactions. Recently, using imaging, integrative proteomics, and cell biology, huntingtin has been defined as a membrane-associated protein, with activities related to axonal trafficking of vesicles and mitochondria. These functions have also been attributed to some huntingtin-interacting proteins. Additionally, discoveries of a membrane association domain and a palmitoylation site in huntingtin reinforce the fact that huntingtin is membrane associated. In Huntington’s disease mouse and fly models, axonal vesicle trafficking is inhibited, and lack of proper uptake of neurotrophic factors may be an important pathological trigger leading to striatal cell death in Huntington’s disease. Here we discuss recent advances from many independent groups and methodologies that are starting to resolve the elusive function of huntingtin in vesicle transport, and evidence that suggests that huntingtin may be directly involved in membrane interactions.

scholarly journals Dysfunction of cAMP-PKA-calcium signaling axis in striatal medium spiny neurons: a role in schizophrenia and Huntington’s disease pathogenesis

2021 ◽  
Author(s):  
Marija Fjodorova ◽  
Zoe Noakes ◽  
Daniel C. De La Fuente ◽  
Adam C. Errington ◽  
Meng Li
Keyword(s):  
Huntington's Disease ◽  
Calcium Signaling ◽  
Huntington’S Disease ◽  
Cortical Neurons ◽  
Medium Spiny Neurons ◽  
Striatal Neurons ◽  
Cell Type ◽  
Direct Role ◽  
Spiny Neurons ◽  
Signaling Axis

SummaryBackgroundStriatal medium spiny neurons (MSNs) are preferentially lost in Huntington’s disease. Genomic studies also implicate a direct role for MSNs in schizophrenia, a psychiatric disorder known to involve cortical neuron dysfunction. It remains unknown whether the two diseases share similar MSN pathogenesis or if neuronal deficits can be attributed to cell type-dependent biological pathways. Transcription factor BCL11B, which is expressed by all MSNs and deep layer cortical neurons, was recently proposed to drive selective neurodegeneration in Huntington’s disease and identified as a candidate risk gene in schizophrenia.MethodsUsing human stem cell-derived neurons lacking BCL11B as a model, we investigated cellular pathology in MSNs and cortical neurons in the context of these disorders. Integrative analyses between differentially expressed transcripts and published GWAS datasets identified cell type-specific disease-related phenotypes.ResultsWe uncover a role for BCL11B in calcium homeostasis in both neuronal types, while deficits in mitochondrial function and protein kinase A (PKA)-dependent calcium transients are detected only in MSNs. Moreover, BCL11B-deficient MSNs display abnormal responses to glutamate and fail to integrate dopaminergic and glutamatergic stimulation, a key feature of striatal neurons in vivo. Gene enrichment analysis reveals overrepresentation of disorder risk genes among BCL11B-regulated pathways, primarily relating to cAMP-PKA-calcium signaling axis and synaptic signaling.ConclusionsOur study indicates that Huntington’s disease and schizophrenia are likely to share neuronal pathogenesis where dysregulation of intracellular calcium levels is found in both striatal and cortical neurons. In contrast, reduction in PKA signaling and abnormal dopamine/glutamate receptor signaling is largely specific to MSNs.

scholarly journals Investigating Antisense Transcription at the HTT Locus

2022 ◽  
Author(s):  
Eugeny A. Elisaphenko ◽  
Anastasia A. Malakhova
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Intracellular Trafficking ◽  
Gene Expression Regulation ◽  
Antisense Transcription ◽  
Dependent Manner ◽  
Rna Seq ◽  
Antisense Transcripts ◽  
Cell Processes ◽  
Different Parts

Antisense transcription is an important mechanism of gene expression regulation. Antisense RNAs play a role in mRNA processing, translation and epigenetic modifications of DNA and histones in the locus of their origin, leading to gene silencing. HTT is a widely expressed gene, the mutation of which causes Huntington’s disease. The product of the gene plays an important role in many cell processes, such as intracellular trafficking, cell division, autophagy, and others. An antisense transcription has been found at the HTT 5’-region. The HTT-AS gene has been reported to affect HTT expression in a Dicer-dependent manner. In this study, we analyzed extensive data from RNA-seq experiments for antisense transcription at the HTT locus. Antisense transcripts corresponding to the HTT-AS gene were not found. However, we revealed a number of antisense transcripts in different parts of the locus that may take part in the regulation and functioning of the HTT gene. Keywords: antisense transcription, HTT-AS, HTTregulation, Huntington’s disease

scholarly journals Targeted Genetic Reduction of Mutant Huntingtin Lessens Cardiac Pathology in the BACHD Mouse Model of Huntington's Disease

2021 ◽  
Vol 8 ◽  
Author(s):  
Saemi Park ◽  
Shu Hon Christopher Luk ◽  
Raj S. Bains ◽  
Daniel S. Whittaker ◽  
Emily Chiem ◽  
...  
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Treatment Strategies ◽  
The Body ◽  
Activity Levels ◽  
Protein Levels ◽  
Pathological Cardiac Hypertrophy ◽  
Expression Of Genes ◽  
Wide Range

Individuals affected by Huntington's disease (HD) present with progressive degeneration that results in a wide range of symptoms, including cardiovascular (CV) dysfunction. The huntingtin gene (HTT) and its product are ubiquitously expressed, hence, the cardiomyopathy could also be driven by defects caused by its mutated form (mHTT) in the cardiomyocytes themselves. In the present study, we sought to determine the contribution of the mHTT expressed in the cardiomyocytes to CV symptoms. We utilized the BACHD mouse model, which exhibits many of the HD core symptoms, including CV dysfunction. This model allows the targeted genetic reduction of mHTT expression in the cardiomyocytes while maintaining the expression of the mHTT in the rest of the body. The BACHD line was crossed with a line of mice in which the expression of Cre recombinase is driven by the cardiac-specific alpha myosin-heavy chain (Myh6) promoter. The offspring of this cross (BMYO mice) exhibited a dramatic reduction in mHTT in the heart but not in the striatum. The BMYO mice were evaluated at 6 months old, as at this age, the BACHD line displays a strong CV phenotype. Echocardiogram measurements found improvement in the ejection fraction in the BMYO line compared to the BACHD, while hypertrophy was observed in both mutant lines. Next, we examined the expression of genes known to be upregulated during pathological cardiac hypertrophy. As measured by qPCR, the BMYO hearts exhibited significantly less expression of collagen1a as well as Gata4, and brain natriuretic peptide compared to the BACHD. Fibrosis in the hearts assessed by Masson's trichrome stain and the protein levels of fibronectin were reduced in the BMYO hearts compared to BACHD. Finally, we examined the performance of the mice on CV-sensitive motor tasks. Both the overall activity levels and grip strength were improved in the BMYO mice. Therefore, we conclude that the reduction of mHtt expression in the heart benefits CV function in the BACHD model, and suggest that cardiomyopathy should be considered in the treatment strategies for HD.

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