Sorcin is an early marker of neurodegeneration, Ca2+ dysregulation and endoplasmic reticulum stress associated to neurodegenerative diseases

Ilaria Genovese, Flavia Giamogante, Lucia Barazzuol, Theo Battista, Annarita Fiorillo, Mattia Vicario, Giuseppina D’Alessandro, Raffaela Cipriani, Cristina Limatola, Daniela Rossi, Vincenzo Sorrentino, Elena Poser, Luciana Mosca, Ferdinando Squitieri, Marzia Perluigi, Andrea Arena, Filip van Petegem, Claudia Tito, Francesco Fazi, Carlotta GiorgiTito Calì, Andrea Ilari, Gianni Colotti

Research output: Contribution to journalArticlepeer-review

Abstract

Dysregulation of calcium signaling is emerging as a key feature in the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD), and targeting this process may be therapeutically beneficial. Under this perspective, it is important to study proteins that regulate calcium homeostasis in the cell. Sorcin is one of the most expressed calcium-binding proteins in the human brain; its overexpression increases endoplasmic reticulum (ER) calcium concentration and decreases ER stress in the heart and in other cellular types. Sorcin has been hypothesized to be involved in neurodegenerative diseases, since it may counteract the increased cytosolic calcium levels associated with neurodegeneration. In the present work, we show that Sorcin expression levels are strongly increased in cellular, animal, and human models of AD, PD, and HD, vs. normal cells. Sorcin partially colocalizes with RyRs in neurons and microglia cells; functional experiments with microsomes containing high amounts of RyR2 and RyR3, respectively, show that Sorcin is able to regulate these ER calcium channels. The molecular basis of the interaction of Sorcin with RyR2 and RyR3 is demonstrated by SPR. Sorcin also interacts with other ER proteins as SERCA2 and Sigma-1 receptor in a calcium-dependent fashion. We also show that Sorcin regulates ER calcium transients: Sorcin increases the velocity of ER calcium uptake (increasing SERCA activity). The data presented here demonstrate that Sorcin may represent both a novel early marker of neurodegenerative diseases and a response to cellular stress dependent on neurodegeneration.

Original languageEnglish
Article number861
JournalCell Death and Disease
Volume11
Issue number10
DOIs
Publication statusPublished - Oct 1 2020

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

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