Activation of Caspase-6 Is Promoted by a Mutant Huntingtin Fragment and Blocked by an Allosteric Inhibitor Compound

Ehrnhoefer, Dagmar E.; Skotte, Niels H.; Reinshagen, Jeanette; Qiu, Xiaofan; Windshügel, Björn; Jaishankar, Priyadarshini; Ladha, S; Petina, Olga A.; Khankischpur, Mehdi; Nguyen, Yen Thi-Kim; Caron, Nicholas S.; Razeto, Adelia; Rheda, Matthias Meyer zu; Deng, Yu; Huynh, Khuong T.; Wittig, Ilka; Gribbon, Philip; Renslo, Adam R.; Geffken, Detlef; Gul, Sheraz; Hayden, Michael R.

doi:10.1016/j.chembiol.2019.07.001

Cited by 13 publications

(19 citation statements)

References 53 publications

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“…AAV CRISPR/Cas9 to truncate the HTT gene at the region corresponding to amino acid 91 and 571 in adult KI-FL mouse brain. These N-terminal HTT fragments are similar to exon 1 HTT and caspase-cleaved products 25,26 , respectively, which have been extensively investigated for their roles in HD pathogenesis [27][28][29][30] . For this experiment, we obtained mice that express Cas9 under the pCAG promoter after Cre-recombination 31 .…”

Section: Resultsmentioning

confidence: 99%

Truncation of mutant huntingtin in knock-in mice demonstrates exon1 huntingtin is a key pathogenic form

Yang

Liang

et al. 2020

Nat Commun

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Polyglutamine expansion in proteins can cause selective neurodegeneration, although the mechanisms are not fully understood. In Huntington's disease (HD), proteolytic processing generates toxic N-terminal huntingtin (HTT) fragments that preferentially kill striatal neurons. Here, using CRISPR/Cas9 to truncate full-length mutant HTT in HD140Q knock-in (KI) mice, we show that exon 1 HTT is stably present in the brain, regardless of truncation sites in full-length HTT. This N-terminal HTT leads to similar HD-like phenotypes and age-dependent HTT accumulation in the striatum in different KI mice. We find that exon 1 HTT is constantly generated but its selective accumulation in the striatum is associated with the age-dependent expression of striatum-enriched HspBP1, a chaperone inhibitory protein. Our findings suggest that tissue-specific chaperone function contributes to the selective neuropathology in HD, and highlight the therapeutic potential in blocking generation of exon 1 HTT.

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Section: Resultsmentioning

confidence: 99%

Truncation of mutant huntingtin in knock-in mice demonstrates exon1 huntingtin is a key pathogenic form

Yang

Liang

et al. 2020

Nat Commun

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“…Overall, however, the differences in pH effects suggest that caspase-6 could be the main executioner caspase in a low pH environment rather than caspase-3. Caspase-6 has a more specialized role in specific physiological contexts compared with caspase-3 and caspase-7 ( 47 , 48 , 49 ). Further analysis of the differences in the dimeric interface among effector caspases would provide clarity regarding the evolutionary changes that resulted in the higher conformational stability of the PCP-6 dimer at low pH.…”

Section: Discussionmentioning

confidence: 99%

Evolution of the folding landscape of effector caspases

Shrestha¹,

Clark²

2021

Journal of Biological Chemistry

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…This hypothesis is supported by mouse genetic data, since caspase-6 hyperactivity is compensated by the genetic inactivation of the D586 site (16). A recent study provided a biochemical mechanism to explain the mechanism: the mHTT1-586 fragment specifically binds to pro-caspase-6 and stabilizes a conformation that leads to its activation (17). Caspase-6 was shown to present highly elevated activity in the postmortem HD striatum and cortex (16), further supporting this hypothesis.…”

Section: Introductionmentioning

confidence: 59%

A pathogenic proteolysis–resistant huntingtin isoform induced by an antisense oligonucleotide maintains huntingtin function

Kim¹,

Lenoir²,

Helfricht³

et al. 2022

JCI Insight

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Huntington's disease (HD) is a late-onset neurological disorder without therapeutics available.Its key pathological mechanism involves the proteolysis of polyglutamine (polyQ)-expanded mutant huntingtin (mHTT), which generates N-terminal fragments containing polyQ, a key contributor to HD pathogenesis. Interestingly, a naturally occurring spliced form of HTT mRNA with truncated exon 12 encodes a huntingtin (HTTΔ12) with a deletion near the caspase-6 cleavage site. In this study, we used a multidisciplinary approach to characterize the therapeutic potential of targeting HTT exon12. We show that HTTΔ12 was resistant to caspase-6 cleavage in both cell-free and tissue lysate assays. However, HTTΔ12 retained overall biochemical and structural properties similar to those of wild-type (wt)-HTT. We generated mice in which HTT exon12 was truncated and found that the canonical exon12 is dispensable for the main physiological functions of HTT, including embryonic development and intracellular trafficking.Finally, we pharmacologically induced HTTΔ12 using the antisense oligonucleotide (ASO) QRX-704. QRX-704 showed predictable pharmacology and efficient biodistribution. In addition, it was stable for several months and inhibited pathogenic proteolysis. Furthermore, QRX-704 treatments resulted in a reduction of HTT aggregation and an increase in dendritic spine count. Thus, ASO-induced HTT exon12 splicing-switching from HTT may provide a novel therapeutic strategy for HD.

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Activation of Caspase-6 Is Promoted by a Mutant Huntingtin Fragment and Blocked by an Allosteric Inhibitor Compound

Cited by 13 publications

References 53 publications

Truncation of mutant huntingtin in knock-in mice demonstrates exon1 huntingtin is a key pathogenic form

Truncation of mutant huntingtin in knock-in mice demonstrates exon1 huntingtin is a key pathogenic form

Evolution of the folding landscape of effector caspases

A pathogenic proteolysis–resistant huntingtin isoform induced by an antisense oligonucleotide maintains huntingtin function

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