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Sorcin is an essential penta-EF hand Ca (II) -binding protein, able to reduce Endoplasmic Reticulum (ER) stress and cell death. X-ray apo and Ca (II)-bound Sorcin structures showed that Ca (II) binding to EF1–3 hands promotes a large conformational change and the exposure of molecular surfaces through which Sorcin interacts with Ryanodine receptors (RYR), Sarco/ER Ca (II)-ATPase (SERCA), Na (I)-Ca (II) exchanger and regulates Ca (II) fluxes.Sorcin is one of the most expressed Ca (II)-binding proteins in the human brain, and is hypothesized to be involved in neurodegenerative diseases. We aim at demonstrating that Sorcin in brain counteracts the increased cytosolic Ca (II) levels associated with neurodegeneration and that for this reason it is overexpressed in HD (Huntington’s Disease).We identified Sorcin interactors by colocalization, coIP and SPR experiments, analysed Ca (II) currents and mitochondria-associated ER membranes (MAMs) and measured Sorcin expression in many biological samples by RT-PCR and Western Blot.Sorcin interacts in a Ca (II)-dependent manner with RYR; it increases both SERCA- and RYR-dependent ER Ca (II) currents and mitochondrial Ca (II) transients; Sorcin increases the number of short MAMs, essential for mitochondrial Ca (II) intake, disrupted in most neurodegenerative diseases, and is able to interact with proteins involved in the Unfolded Protein Response, i.e. ATF6, eIF2a and Sigma1R, localized in MAM. Finally, we found increased Sorcin expression levels in fibroblasts from HD patients and post-mortem cortex tissue of HD subjects.Our preliminary results show that sorcin, which controls Ca (II) flux across cell compartments, is overexpressed in neurons to counteract Ca (II) unbalance caused by HD. These findings indicate that Sorcin is a novel, promising HD marker and represents a defence from cellular stress dependent on neurodegeneration.