THE EFFECT OF MUTANT HUNTINGTIN ON CLEAVAGE OF CREST BY CALPAIN-2 AND ITS CYTOTOXITY
Neuronal cell cycle re-entry is a pathological hallmark of Huntington’s disease (HD) and other neurodegenerative disorders. Calcium-responsive transactivator(CREST) has been found to play a critical role in dendritic development through calcium-dependent transcriptional regulation and to form a fun...
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| Format: | Article |
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| Language: | English |
| Published: |
PAGEPress Publications
2025-08-01
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| Series: | European Journal of Histochemistry |
| Subjects: | |
| Online Access: | https://www.ejh.it/ejh/article/view/4292 |
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| Summary: | Neuronal cell cycle re-entry is a pathological hallmark of Huntington’s disease (HD) and other neurodegenerative disorders. Calcium-responsive transactivator(CREST) has been found to play a critical role in dendritic development through calcium-dependent transcriptional regulation and to form a functional complex with p300 and p53 to suppress retinoblastoma protein (Rb) phosphorylation and cyclin expression, thereby arresting the cell cycle and promoting neuronal differentiation. Here we demonstrated that mutant huntingtin (mHtt) significantly reduced full-length CREST levels while inducing the production of truncated CREST fragments. This process was blocked by inhibitors of calpain-1 and -2, suggesting calpain involvement. Using mass spectrometry, co-IP, and in vitro pull-down assays, we provided direct evidence that mHtt enhanced the interaction between calpain-2 and CREST, leading to increased CREST cleavage which generated a toxic C-terminal fragment that accumulated abnormally in the nucleus. Furthermore, we designed a TAT peptide targeting the calpain-2 cleavage site of CREST, which effectively prevented CREST degradation and significantly ameliorated mHtt-induced pathological phenotypes in N2a cells, including neuronal death, neurite retraction, and aberrant Rb phosphorylation. Collectively, our findings establish CREST as a specific substrate of calpain-2 and reveal a novel mechanism by which mHtt promotes neuronal cell cycle re-entry and neurotoxicity through calpain-2-mediated CREST degradation. The toxic C-terminal fragment of CREST exhibits distinct pathological properties. Importantly, our study identifies the calpain cleavage site on CREST as a potential therapeutic target for HD intervention. Targeting this site with specific inhibitors or peptide blockers may represent a promising strategy to prevent mHtt-induced neuronal dysfunction and cell death.
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| ISSN: | 1121-760X 2038-8306 |