Calpain Activation in Huntington's Disease

Buck Institute for Age Research, Novato, California 94945, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 07/2002; 22(12):4842-9.
Source: PubMed


Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG expansion that results in elongation of the polyglutamine tract at the N terminus of huntingtin (Htt). Abnormal proteolytic processing of mutant Htt has been implicated as a critical step in the initiation of HD. The protease(s) involved in this process has not been fully characterized. Here we report that activated calpain was detected in the caudate of human HD tissue but not in age-matched controls. In addition, one of the major N-terminal Htt proteolytic fragments found in human HD tissue appears to be derived from calpain cleavage. Htt fragments in HD lysates were similar in size to those produced by exposure of in vitro-translated Htt to exogenous calpain. Incubation of in vitro-translated Htt with calpain generated a cascade of cleavage events with an initial intermediate cleavage product at 72 kDa and a final cleavage product at 47 kDa. The rate of cleavage of Htt by calpain was polyglutamine-length-dependent. These results suggest that cleavage of Htt in human HD tissue is mediated in part by the Ca2+-activated neutral protease, calpain.

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    • "Interestingly, an age-dependent attenuation of calpain activity was observed in an HD mouse model, suggesting alterations in calcium signaling mechanism with disease progression [70]. Furthermore, wild-type and mutant huntingtin were identified as calpain substrates and calpain-dependent proteolytic cleavage products of huntingtin were detected in murine and human HD tissue [25] [27] [46] [71]. Caspase-3 cleavage derived huntingtin fragments undergo further proteolysis by calpains, generating smaller products and suggesting a proteolytic pathway of serial processing events [20]. "
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    ABSTRACT: The history of polyglutamine diseases dates back approximately 20 years to the discovery of a polyglutamine repeat in the androgen receptor of SBMA followed by the identification of similar expansion mutations in Huntington’s disease, SCA1, DRPLA, and the other spinocerebellar ataxias. This common molecular feature of polyglutamine diseases suggests shared mechanisms in disease pathology and neurodegeneration of disease specific brain regions. In this review, we discuss the main pathogenic pathways including proteolytic processing, nuclear shuttling and aggregation, mitochondrial dysfunction, and clearance of misfolded polyglutamine proteins and point out possible targets for treatment.
    Full-text · Article · Sep 2014 · BioMed Research International
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    • "Elevated Ex- NMDAR activity occurs early in the YAC128 mouse model of HD and contributes to mtHtt-induced striatal pathology (Milnerwood et al., 2010; Okamoto et al., 2009). Ca 2+ dependent pathways closely linked to cell death are also dysregulated prior to phenotype onset and contribute to neuronal toxicity in HD (Cowan et al., 2008; Fan et al., 2012; Gafni and Ellerby, 2002; Gladding et al., 2012; Milnerwood et al., 2010; Wu et al., 2011; Zhang et al., 2008). Here, we aimed to demonstrate a causal link between Ex-NMDAR activity and aberrant intracellular Ca 2+ signaling in HD. "
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    ABSTRACT: In the YAC128 mouse model of Huntington disease (HD), elevated extrasynaptic NMDA receptor (Ex-NMDAR) expression contributes to the onset of striatal dysfunction and atrophy. A shift in the balance of synaptic-extrasynaptic NMDAR signaling and localization is paralleled by early stage dysregulation of intracellular calcium signaling pathways, including calpain and p38 MAPK activation, that couple to pro-death cascades. However, whether aberrant calcium signaling is a consequence of elevated Ex-NMDAR expression in HD is unknown. Here, we aimed to identify calcium-dependent pathways downstream of Ex-NMDARs in HD. Chronic (2-month) treatment of YAC128 and WT mice with memantine (1 and 10mg/kg/d), which at a low dose selectively blocks Ex-NMDARs, reduced striatal Ex-NMDAR expression and current in 4-month old YAC128 mice without altering synaptic NMDAR levels. In contrast, calpain activity was not affected by memantine treatment, and was elevated in untreated YAC128 mice at 1.5 months but not 4 months of age. In YAC128 mice, memantine at 1mg/kg/d rescued CREB shut-off, while both doses suppressed p38 MAPK activation to WT levels. Taken together, our results indicate that Ex-NMDAR activity perpetuates increased extrasynaptic NMDAR expression and drives dysregulated p38 MAPK and CREB signaling in YAC128 mice. Elucidation of the pathways downstream of Ex-NMDARs in HD could help provide novel therapeutic targets for this disease.
    Full-text · Article · Nov 2013 · Neurobiology of Disease
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    • "In post-mortem brains of HD patients, aggregates are enriched with N-terminal truncated forms of polyQ-hHtt [9]. Therefore, blocking mutant Huntingtin proteolysis was found to be beneficial in treating HD mice [7] [10] [11]. In general, HD models with short truncations of the expanded Htt protein present more severe phenotypes that also appear earlier than hHtt full-length expressing models [8] [13]. "
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    ABSTRACT: Huntington's disease (HD) is caused by the abnormal expansion of the polyglutamine tract in the human Huntingtin protein (polyQ-hHtt). Although this mutation behaves dominantly, huntingtin loss of function also contributes to HD pathogenesis. Indeed, wild-type Huntingtin plays a protective role with respect to polyQ-hHtt induced defects. The question that we addressed here is what part of the wild-type Huntingtin is responsible for these protective properties. We first screened peptides from the Huntingtin protein in HeLa cells and identified a 23 aa peptide (P42) that inhibits polyQ-hHtt aggregation. P42 is part of the endogenous Huntingtin protein and lies within a region rich in proteolytic sites that plays a critical role in the pathogenesis process. Using a Drosophila model of HD, we tested the protective properties of this peptide on aggregation, as well as on different polyQ-hHtt induced neuronal phenotypes: eye degeneration (an indicator of cell death), impairment of vesicular axonal trafficking, and physiological behaviors such as larval locomotion and adult survival. Together, our results demonstrate high protective properties for P42 in vivo, in whole animals. These data also demonstrate a specific role of P42 on Huntington's disease model, since it has no effect on other models of polyQ-induced diseases, such as spinocerebellar ataxias. Altogether our data show that P42, a 23 aa-long hHtt peptide, plays a protective role with respect to polyQ-hHtt aggregation as well as cellular and behavioral dysfunctions induced by polyQ-hHtt in vivo. Our study also confirms the correlation between polyQ-hHtt aggregation and neuronal defects. Finally, these results strongly suggest a therapeutic potential for P42, specific of Huntington's disease.
    Full-text · Article · Jul 2013 · PLoS ONE
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