Neurodegeneration: a mechanism links Huntington's to other diseases

A common neurodegeneration marker for Huntington's, Parkinson's, and Alzheimer's disease


A recent study identifies a new biochemical mediator potentially able to represent a marker of neurodegeneration in Huntington's disease, Alzheimer's disease and Parkinson's disease. 

It is called Sorcin and it is a soluble protein, expressed in most cells, particularly in neurons and glia, responsible for the regulation of calcium fluxes and its metabolism within the cell. Calcium is an important ion for several cellular processes, including muscle contraction, release of neurotransmitters, and the life of nerve cells. It is necessary for cells to maintain a certain level of calcium in the cytoplasm and sub-cellular organelles (nucleus, mitochondrion, and endoplasmic reticulum). Sorcin helps to maintain this balance.

Many neurodegenerative diseases have in common an alteration of calcium metabolism and consequent dysfunction, degeneration and death of nerve cells. The aim of the study "Sorcin is an early marker of neurodegeneration, Ca 2+ dysregulation and endoplasmic reticulum stress associated to neurodegenerative diseases" was to better understand the role that Sorcin plays in three neurodegenerative diseases: Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD). 

In this study were used different models both animal and cellular from patients with these 3 different neurodegenerative diseases. A complex work that has involved many different techniques and different teams of researchers. Analyses were performed on different cell lines: on controls in which the calcium flux concentration was measured in "normal" lines and on lines from patients in which sorcin was added or subtracted (silenced). 

The Huntington's Unit of IRCCS Casa Sollievo della Sofferenza, CSS-Mendel section in Rome, led by Professor Ferdinando Squitieri, provided autopsy samples of cerebral cortex of post-mortem patients, from people without and with Huntington's disease (early and very advanced). 

It was noted that this protein is expressed in higher amounts in cellular models altered by the disease or in patients' cells with neurodegenerative diseases.

Sorcin levels result altered already in the early stages of the disease: there is an increase in its production from the first manifestation of symptoms and then it returns to levels similar to those of healthy cells. The overproduction of Sorcin could represent one of the ways that the cell has to cope with the stress induced by the early consequences of neurodegeneration and from the consequent cellular damage. 

In Huntington's disease, the huntingtin protein is impaired due to an expanded stretch of polyglutamines (PolyQ). Mutated huntingtin results in a number of metabolic cellular dysregulations, including calcium dysregulation, which causes cellular stress and subsequent nerve cell death. It has been noticed that even in this case, cells try to resist this induced stress through the higher production of sorcin to buffer the negative effect caused by huntingtin. 

With this study we hypothesize that Sorcin may be an early neurodegeneration marker for 3 different neurodegenerative diseases, including Huntington's disease. In this case, Sorcin interacts with sub-cellular components that are well known to researchers studying Huntington's disease: the Endoplasmic Reticulum, Mitochondria and, most importantly, the Sigma-1 receptor (S1R). "This receptor is, in particular, the focus of the global scientific community's attention" says Ferdinando Squitieri, co-author of the study, "because an investigational drug currently being tested, Pridopidine, uses exactly the S1R to exert its neuroprotective effect." The CSS-Mendel Institute is currently involved in the PROOF-HD study to test the use of Pridopidine in a Phase 3 trial in Huntington's disease and patient recruitment is ongoing. 

The Sorcin research was published in the Nature journal Cell Death and Disease.

Here the complete article.