ArticlePharmacological reports : PR2026
Dysregulation of store-operated calcium entry in fibroblast lines from adult and juvenile-onset Huntington's disease patients.
Article in Pharmacological reports : PR, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundThe pathology of Huntington's disease (HD) is marked by the aggregation of mutant huntingtin protein (mHTT), which results from expanded polyglutamine (polyQ) residues encoded by CAG repeats in the HTT gene. These repeats are differentially elongated in adult- and juvenile-onset HD. In striatal neurons, the mHTT disrupts cellular mechanisms such as store-operated calcium entry (SOCE), a process in which endoplasmic reticulum Ca²⁺ depletion triggers extracellular Ca²⁺ influx; however, this process can also be affected in peripheral cells. The aim of this study was to evaluate SOCE in fibroblasts derived from both HD onset patients and age-related controls.
methodsWe conducted SOCE analysis in dermal fibroblasts from 12 HD patients (including adult- and juvenile-onset subtypes) and age-related healthy controls using Fura-2 AM ratiometric imaging paired with EGTA-based extracellular calcium chelation protocols. To evaluate SOCE response, we administered two SOC channel inhibitors, 6-bromo-N-(2-phenylethyl)-2,3,4,9-tetrahydro-1 H-carbazol-1-amine hydrochloride (C
resultsIn healthy human fibroblast lines, a decline in SOCE was observed between juvenile and adult individuals. In fibroblast lines from adult-onset HD patients (premanifest, early manifest, and manifest stages), we observed increased SOC channel activity. Conversely, juvenile-onset HD fibroblast lines exhibited reduced SOC channel activity compared to controls. Notably, SOCE dysregulation was independent of CAG repeat length in HD lines. Both SOC channel inhibitors attenuated SOCE in adult-onset HD lines.
conclusionThe mHTT upregulates SOCE in adult-onset HD fibroblasts and downregulates it in juvenile-onset HD fibroblast lines; however, SOCE levels do not correlate with the length of CAG repeats encoding mHTT. Despite opposing trends compared to age-related controls, similar levels of SOCE in both HD-onset fibroblasts were detected. Both C
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