Browse
Submit Data
Databases
API
Help

Dataset Information

23 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Small-molecule suppression of calpastatin degradation reduces neuropathology in models of Huntington's disease.

ABSTRACT: Mitochondrial dysfunction is a common hallmark of neurological disorders, and reducing mitochondrial damage is considered a promising neuroprotective therapeutic strategy. Here, we used high-throughput small molecule screening to identify CHIR99021 as a potent enhancer of mitochondrial function. CHIR99021 improved mitochondrial phenotypes and enhanced cell viability in several models of Huntington's disease (HD), a fatal inherited neurodegenerative disorder. Notably, CHIR99201 treatment reduced HD-associated neuropathology and behavioral defects in HD mice and improved mitochondrial function and cell survival in HD patient-derived neurons. Independent of its known inhibitory activity against glycogen synthase kinase 3 (GSK3), CHIR99021 treatment in HD models suppressed the proteasomal degradation of calpastatin (CAST), and subsequently inhibited calpain activation, a well-established effector of neural death, and Drp1, a driver of mitochondrial fragmentation. Our results established CAST-Drp1 as a druggable signaling axis in HD pathogenesis and highlighted CHIR99021 as a mitochondrial function enhancer and a potential lead for developing HD therapies.

SUBMITTER: Hu D

PROVIDER: S-EPMC8421361 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Suppression of MAPK11 or HIPK3 reduces mutant Huntingtin levels in Huntington's disease models.

Project description:Most neurodegenerative disorders are associated with accumulation of disease-relevant proteins. Among them, Huntington disease (HD) is of particular interest because of its monogenetic nature. HD is mainly caused by cytotoxicity of the defective protein encoded by the mutant Huntingtin gene (HTT). Thus, lowering mutant HTT protein (mHTT) levels would be a promising treatment strategy for HD. Here we report two kinases HIPK3 and MAPK11 as positive modulators of mHTT levels both in cells and in vivo. Both kinases regulate mHTT via their kinase activities, suggesting that inhibiting these kinases may have therapeutic values. Interestingly, their effects on HTT levels are mHTT-dependent, providing a feedback mechanism in which mHTT enhances its own level thus contributing to mHTT accumulation and disease progression. Importantly, knockout of MAPK11 significantly rescues disease-relevant behavioral phenotypes in a knockin HD mouse model. Collectively, our data reveal new therapeutic entry points for HD and target-discovery approaches for similar diseases.

| S-EPMC5717400 | biostudies-literature

Identification and evaluation of small molecule pan-caspase inhibitors in Huntington's disease models.

Project description:Huntington's Disease (HD) is characterized by a mutation in the huntingtin (Htt) gene encoding an expansion of glutamine repeats on the N terminus of the Htt protein. Numerous studies have identified Htt proteolysis as a critical pathological event in HD postmortem human tissue and mouse HD models, and proteases known as caspases have emerged as attractive HD therapeutic targets. We report the use of the substrate activity screening method against caspase-3 and -6 to identify three novel, pan-caspase inhibitors that block proteolysis of Htt at caspase-3 and -6 cleavage sites. In HD models these irreversible inhibitors suppressed Hdh(111Q/111Q)-mediated toxicity and rescued rat striatal and cortical neurons from cell death. In this study, the identified nonpeptidic caspase inhibitors were used to confirm the role of caspase-mediated Htt proteolysis in HD. These results further implicate caspases as promising targets for HD therapeutic development.

| S-EPMC3035168 | biostudies-literature

Huntington's disease brain-derived small RNAs recapitulate associated neuropathology in mice

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-02-16 | GSE165667 | GEO

A small molecule p75NTR ligand normalizes signalling and reduces Huntington's disease phenotypes in R6/2 and BACHD mice.

Project description:Decreases in the ratio of neurotrophic versus neurodegenerative signalling play a critical role in Huntington’s disease (HD) pathogenesis and recent evidence suggests that the p75 neurotrophin receptor (NTR) contributes significantly to disease progression. p75NTR signalling intermediates substantially overlap with those promoting neuronal survival and synapse integrity and with those affected by the mutant huntingtin (muHtt) protein. MuHtt increases p75NTR-associated deleterious signalling and decreases survival signalling suggesting that p75NTR could be a valuable therapeutic target. This hypothesis was investigated by examining the effects of an orally bioavailable, small molecule p75NTR ligand, LM11A-31, on HD-related neuropathology in HD mouse models (R6/2, BACHD). LM11A-31 restored striatal AKT and other pro-survival signalling while inhibiting c-Jun kinase (JNK) and other degenerative signalling. Normalizing p75NTR signalling with LM11A-31 was accompanied by reduced Htt aggregates and striatal cholinergic interneuron degeneration as well as extended survival in R6/2 mice. The p75NTR ligand also decreased inflammation, increased striatal and hippocampal dendritic spine density, and improved motor performance and cognition in R6/2 and BACHD mice. These results support small molecule modulation of p75NTR as an effective HD therapeutic strategy. LM11A-31 has successfully completed Phase I safety and pharmacokinetic clinical trials and is therefore a viable candidate for clinical studies in HD.

| S-EPMC5418739 | biostudies-literature

Huntington's disease brain-derived small RNAs recapitulate associated neuropathology in mice [human-miRNA]

Project description:Progressive motor alterations and selective death of striatal medium spiny neurons (MSNs) are key pathological hallmarks of Huntington's disease (HD), a neurodegenerative condition caused by a CAG trinucleotide repeat expansion in the coding region of the huntingtin (HTT) gene. Most research has focused on the pathogenic effects of the resultant protein product(s); however, growing evidence indicates that expanded CAG repeats within mutant HTT mRNA and derived small CAG repeat RNAs (sCAG) participate in HD pathophysiology. The individual contribution of protein versus RNA toxicity to HD pathophysiology remains largely uncharacterized and the role of other classes of small RNAs (sRNA) that are strongly perturbed in HD is uncertain. Here, have injected vehicle, CTL-sRNA (obtained from non-affected individuals) or HD-sRNA (obtained from patients with HD) from different brain areas (putamen, PT; cortex, CTX and cerebellum, CB) into the striatum of wild type (WT) mice and demonstrate that sRNA produced in the putamen and cortex of HD patients are sufficient to induce HD pathology in vivo. We have performed small RNA (sRNA) sequencing of the human samples used for injection. Here we describe the procedure to obtain and sequence human sRNA isolated from the different brain areas.

2021-02-16 | GSE165663 | GEO

The Emerging Landscape of Natural Small-molecule Therapeutics for Huntington's Disease.

Project description:Huntington's disease (HD) is a rare and fatal neurodegenerative disorder with no diseasemodifying therapeutics. HD is characterized by extensive neuronal loss and is caused by the inherited expansion of the huntingtin (HTT) gene that encodes a toxic mutant HTT (mHTT) protein having expanded polyglutamine (polyQ) residues. Current HD therapeutics only offer symptomatic relief. In fact, Food and Drug Administration (FDA) approved two synthetic small-molecule VMAT2 inhibitors, tetrabenazine (1) and deutetrabenazine (2), for managing HD chorea and various other diseases in clinical trials. Therefore, the landscape of drug discovery programs for HD is evolving to discover disease- modifying HD therapeutics. Likewise, numerous natural products are being evaluated at different stages of clinical development and have shown the potential to ameliorate HD pathology. The inherent anti-inflammatory and antioxidant properties of natural products mitigate the mHTT-induced oxidative stress and neuroinflammation, improve mitochondrial functions, and augment the anti-apoptotic and pro-autophagic mechanisms for increased survival of neurons in HD. In this review, we have discussed HD pathogenesis and summarized the anti-HD clinical and pre-clinical natural products, focusing on their therapeutic effects and neuroprotective mechanism/s.

| S-EPMC10227909 | biostudies-literature

Huntington's disease brain-derived small RNAs recapitulate associated neuropathology in mice [Mouse RNA-seq]

Project description:Progressive motor alterations and selective death of striatal medium spiny neurons (MSNs) are key pathological hallmarks of Huntington's disease (HD), a neurodegenerative condition caused by a CAG trinucleotide repeat expansion in the coding region of the huntingtin (HTT) gene. Most research has focused on the pathogenic effects of the resultant protein product(s); however, growing evidence indicates that expanded CAG repeats within mutant HTT mRNA and derived small CAG repeat RNAs (sCAG) participate in HD pathophysiology. The individual contribution of protein versus RNA toxicity to HD pathophysiology remains largely uncharacterized and the role of other classes of small RNAs (sRNA) that are strongly perturbed in HD is uncertain. Here, have injected vehicle (VEH), CTL-sRNA-PT (obtained from the putamen of non-affected individuals) or HD-sRNA-PT (obtained from the putamen of patients with HD) into the striatum of wild type (WT) mice, and demonstrate that sRNA produced in the putamen and cortex of HD patients are sufficient to induce HD pathology in vivo, including transcriptional alterations. To reveal the transcriptional changes produced by sCAG, we co-injected human sRNAs with a locked nucleic acid (LNA) modified anti-sense oligonucleotide complementary to sCAG (HD-sRNA-PT + LNA-CTG) or an analogous scrambled LNA (HD-sRNA-PT + LNA-SCB). We have performed mRNA-seq in the different experimental groups: Vehicle, CTL-sRNA-PT, HD-sRNA-PT, HD-sRNA-PT + LNA-CTG, and HD-sRNA-PT + LNA-SCB. Here we describe the procedure to obtain and sequence human sRNA dataset isolated from the different brain areas.

2021-02-16 | GSE165658 | GEO

Huntington's disease phenotypes are improved via mTORC1 modulation by small molecule therapy.

Project description:Huntington's Disease (HD) is a dominantly inherited neurodegenerative disease for which the major causes of mortality are neurodegeneration-associated aspiration pneumonia followed by cardiac failure. mTORC1 pathway perturbations are present in HD models and human tissues. Amelioration of mTORC1 deficits by genetic modulation improves disease phenotypes in HD models, is not a viable therapeutic strategy. Here, we assessed a novel small molecule mTORC1 pathway activator, NV-5297, for its improvement of the disease phenotypes in the N171-82Q HD mouse model. Oral dosing of NV-5297 over 6 weeks activated mTORC1, increased striatal volume, improved motor learning and heart contractility. Further, the heart contractility, heart fibrosis, and survival were improved in response to the cardiac stressor isoprenaline when compared to vehicle-treated mice. Cummulatively, these data support mTORC1 activation as a therapeutic target in HD and consolidates NV-5297 as a promising drug candidate for treating central and peripheral HD phenotypes and, more generally, mTORC1-deficit related diseases.

| S-EPMC9423655 | biostudies-literature

Small molecules enhance autophagy and reduce toxicity in Huntington's disease models.

Project description:The target of rapamycin proteins regulate various cellular processes including autophagy, which may play a protective role in certain neurodegenerative and infectious diseases. Here we show that a primary small-molecule screen in yeast yields novel small-molecule modulators of mammalian autophagy. We first identified new small-molecule enhancers (SMER) and inhibitors (SMIR) of the cytostatic effects of rapamycin in Saccharomyces cerevisiae. Three SMERs induced autophagy independently of rapamycin in mammalian cells, enhancing the clearance of autophagy substrates such as mutant huntingtin and A53T alpha-synuclein, which are associated with Huntington's disease and familial Parkinson's disease, respectively. These SMERs, which seem to act either independently or downstream of the target of rapamycin, attenuated mutant huntingtin-fragment toxicity in Huntington's disease cell and Drosophila melanogaster models, which suggests therapeutic potential. We also screened structural analogs of these SMERs and identified additional candidate drugs that enhanced autophagy substrate clearance. Thus, we have demonstrated proof of principle for a new approach for discovery of small-molecule modulators of mammalian autophagy.

| S-EPMC2635561 | biostudies-literature

A Novel Small-Molecule Inhibitor of Endosomal TLRs Reduces Inflammation and Alleviates Autoimmune Disease Symptoms in Murine Models.

Project description:Toll-like receptors (TLRs) play a fundamental role in the inflammatory response against invading pathogens. However, the dysregulation of TLR-signaling pathways is implicated in several autoimmune/inflammatory diseases. Here, we show that a novel small molecule TLR-inhibitor (TAC5) and its derivatives TAC5-a, TAC5-c, TAC5-d, and TAC5-e predominantly antagonized poly(I:C) (TLR3)-, imiquimod (TLR7)-, TL8-506 (TLR8)-, and CpG-oligodeoxynucleotide (TLR9)-induced signaling pathways. TAC5 and TAC5-a significantly hindered the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), reduced the phosphorylation of mitogen-activated protein kinases, and inhibited the secretion of tumor necrosis factor-α (TNF-α) and interleukin-6. Besides, TAC5-a prevented the progression of psoriasis and systemic lupus erythematosus (SLE) in mice. Interestingly, TAC5 and TAC5-a did not affect Pam3CSK4 (TLR1/2)-, FSL-1 (TLR2/6)-, or lipopolysaccharide (TLR4)-induced TNF-α secretion, indicating their specificity towards endosomal TLRs (TLR3/7/8/9). Collectively, our data suggest that the TAC5 series of compounds are potential candidates for treating autoimmune diseases such as psoriasis or SLE.

| S-EPMC7407930 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data