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Genetic Master Switch Identified as Possible Target for Early-Stage Parkinsonís Therapy

Scientists have recently found evidence to suggest that metabolic pathways are impaired Parkinson’s disease (PD) and a master gene may partially restore the pathway’s normal function.  Scientists say that this gene may be a target for new therapies for Parkinson’s, as reported in the October 6 issue of Science Translational Medicine.

Parkinson’s disease, in its early stages, notably affects neurons in an area of the brain called the substantia nigra.  In effort to understand why these cells are affected by PD, an international consortium of researchers led by Clemens R. Scherzer, M.D., at Harvard Medical School, assessed autopsy data in search of changes to the biological pathways of neurons in this area of the brain.  

They analyzed gene activity in 322 brain tissue and 88 blood samples from people who had died with PD, with PD brain changes but no symptoms, or without PD.  The scientists used an innovative approach called systems biology that allowed them to analyze the activity of gene sets—groups of genes that encode parts of the same biological pathway—rather than looking at genes one by one. 

 

Results

  • The scientists identified 10 new gene sets linked to PD 
  • These gene sets are all related to mitochondrial energy production, or to the reproduction and maintenance of the mitochondria themselves.
  • The activity of these genes was lower than normal in brain cells from people with PD. When these genes shut down, brain cells are deprived of fuel and become damaged or die. This means that many of the metabolic pathways within the substantia nigra region of the brain are impaired. 
  • A master gene called PGC-1α was identified, which regulates the activity of these other genes.
  • In experiments with rat brain cells exposed to the pesticide rotenone, which is toxic to mitochondria, activating PGC-1α limited cell damage and death.
  • Activating PGC-1α in rat cells with a mutated form of α-synuclein known to cause PD in humans also offered some, though not complete, protection from cell death.

 

What Does it Mean?

This study emphasizes the importance of data that can be obtained from autopsies.  It provides additional information to suggest that mitochondrial dysfunction plays a role in PD and may begin early in the development of PD, before symptoms are evident.  Mitochondria are structures inside cells that take nutrients and metabolize them into energy that a cell can use.

As a result, mitochondrial function may one day offer a way to diagnose PD earlier.  In addition, these results provide hope that a therapy that boosts the health of mitochondria could prevent or slow the loss of neurons that leads to PD symptoms.  The master switch identified, the gene PGC-1α, is already a target for drugs in development to treat diabetes and other diseases.  The fact that pharmaceutical companies have experience in working on such therapies might speed the process of drug discovery for PD.

 

Reference: Zheng et al. PGC-1α, a potential therapeutic target for early intervention in Parkinson's disease. Sci Transl Med (2010) vol. 2 (52) pp. 52ra73 (http://dx.doi.org/10.1126/scitranslmed.3001059).


Source Date: Nov 05 2010