SORCIN RESCUES CA (II) DYSREGULATION AND ENDOPLASMIC RETICULUM STRESS IN HUNTINGTON'S DISEASE

Background Sorcin is an essential penta-EF hand Ca (II) -binding protein, able to reduce Endoplasmic Reticulum (ER) stressand cell death. X-ray apo and Ca (II)-bound Sorcin structuresshowed that Ca (II) binding to EF1–3 hands promotes a largeconformational change and the exposure of molecular surfacesthrough which Sorcin interacts with Ryanodine receptors(RYR), Sarco/ER Ca (II)-ATPase (SERCA), Na (I)-Ca (II)exchanger and regulates Ca (II) fluxes.Aims Sorcin is one of the most expressed Ca (II)-binding proteins in the human brain, and is hypothesized to be involvedin neurodegenerative diseases. We aim at demonstrating thatSorcin in brain counteracts the increased cytosolic Ca (II) levels associated with neurodegeneration and that for this reasonit is overexpressed in HD (Huntington’s Disease).Methods We identified Sorcin interactors by colocalization, coIPand SPR experiments, analysed Ca (II) currents and mitochondriaassociated ER membranes (MAMs) and measured Sorcin expression in many biological samples by RT-PCR and Western Blot.Results Sorcin interacts in a Ca (II)-dependent manner withRYR; it increases both SERCA- and RYR-dependent ER Ca(II) currents and mitochondrial Ca (II) transients; Sorcinincreases 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 theUnfolded 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-mortemcortex tissue of HD subjects.Conclusions Our preliminary results show that sorcin, whichcontrols Ca (II) flux across cell compartments, is overexpressed in neurons to counteract Ca (II) unbalance caused byHD. These findings indicate that Sorcin is a novel, promisingHD marker and represents a defence from cellular stressdependent on neurodegeneration.