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Parkinsonís DJ-1 Gene Protects Cells from Toxic Oxidative Stress

Research published in the November 10, 2010 online issue of Nature reveals new details of the role the gene DJ-1 plays in protecting dopamine neurons, and how mutations in this gene can cause Parkinson’s disease (PD).  The study also shows how a type of drug known as a calcium channel blocker can preempt DJ-1 and potentially prevent the nerve cell death that results in PD.  

In Parkinson’s, cells known as dopamine neurons die in an area of the brain called the substantia nigra.  These cells are probably particularly sensitive to stresses on their mitochondria, the internal structures that produce energy.  The reason for this vulnerability has been a focus of much research.

Earlier research by D. James Surmeier, Ph.D., at Northwestern University’s Feinberg School of Medicine showed that the mitochondria of dopamine cells are especially hard-working.  Unlike neighboring neurons, dopamine cells transport calcium ions across their membranes when they are active. But too much calcium inside a cell can be toxic.  So a dopamine neuron’s mitochondria must generate an unusually large amount of energy to pump excess calcium out of the cell.

The new study, led by Jaime Guzman, Ph.D., in Dr. Surmeier’s laboratory, examined what happens to the mitochondria as calcium enters dopamine cells by looking at the electrical properties of the mitochondria and the role of DJ-1.  Mutations in the gene DJ-1 are an exceptionally rare cause of familial early-onset PD.  The experiments were carried out in laboratory mice. 


The researchers found that:

  • Calcium entering through so-called L-type channels in dopamine cells induced stress in mitochondria called oxidative stress.  
  • Mitochondria responding to this oxidative stress “flickered” as they were knocked slightly off balance electrically.
  • This “flickering” was observed only in dopamine neurons of the substantia nigra and not in other types of similarly active neurons.
  • Normally mitochondria can limit the damage from oxidative stress.
  • Inactivating the gene DJ-1 (PARK7), known to cause PD, knocked out the ability of the mitochondria to control oxidative stress.
  • Blocking calcium entry in mice with inactive DJ-1 blocked the rise in oxidative stress. 


What Does It Mean?

The new research aims to explain why the cells that die in PD are more sensitive to toxic oxidative stress than other brain cells:  calcium entering the cells through L-type channels delivers a first blow that leaves them vulnerable to further injury.  

This study supports the idea that drugs that block L-type channels may help alleviate mitochondrial stress and help prevent the death of these neurons, perhaps even protecting against the progression of PD.  One such medication is isradipine, a drug already used to treat high blood pressure, which is in early clinical trials for its neuroprotective effects in PD (at the PDF-funded Columbia University center, among others).  While this study was performed on laboratory mice, the new understanding of the calcium and DJ-1’s role in the disease pathway reported may help design new therapeutics that are specifically effective for PD.


Source Date: Dec 02 2010