Genetics Clues May Lead New Treatment for Parkinson’s Disease

Parkinson’s disease (PD) is a neurodegenerative disorder in which mainly nerve cells in the substantia nigra of the brain die. This region is a central area of the brain that is involved in the control of movements. The cells in this area produce a neurotransmitter (messenger molecule between nerve cells) that is called dopamine and why these cells specifically succumb in PD is not completely clear. However, recent research produced hints that the dopamine-producing cells in the substantia nigra are particularly sensitive to disruptions in the energy production of the cells.

Brain cells in general are very dependent on well-working energy production machinery, as their energy requirements are among the highest in the body: the brain uses about 20% of the body’s energy, while it has only about 2% of the body’s weight which might make the brain more sensitive than other organs to disruptions in this system. It has been known since a while that the cell’s power plants called mitochondria often show defects in PD patients.

A study that was recently published in the journal Science Translational Medicine now shows even more conclusive evidence that energy production is impaired in this disorder. The researchers analyzed the expression of genes in tissue samples collected from diseased PD patients and found 10 different sets of genes showing decreased expression in the patients that was not found in healthy controls. Interestingly, all ten sets of genes pointed to one common activator as a master-regulator of cellular energy production, a protein called peroxisome proliferator–activated receptor g coactivator-1a (PGC-1a). It is known since longer that activation of PGC-1a can treat PD in mouse models of the disease. This decrease in action of the PGC-1a gene that ultimately leads to the demise of the dopamine producing neurons in the substantia nigra probably starts years before the appearance of the first symptoms of the disease.

Still, these findings open new avenues in treating early disease and preventing further damage to the nerve cells and progression of the disorder. Medications that can activate PGC-1a are already in use for other diseases like for example diabetes. Unfortunately it is not possible to simply give these medications to PD patients, as they can only work if they can get to the brain. A biological barrier that protects our brains from toxic substances that are in the blood stream like alcohol, drugs, and toxic degradation products of the metabolism called the blood-brain-barrier also keeps these medications out of the brain. Nevertheless, the knowledge what kind of medications can activate PGC-1a can lead to a faster development of drugs that can do the same and reach the necessary areas in the brain to work for PD patients.

References

Zheng B, Liao Z, Locascio JJ, Lesniak KA, Roderick SS, Watt ML, Eklund AC, Zhang-James Y, Kim PD, Hauser MA, Grünblatt E, Moran LB, Mandel SA, Riederer P, Miller RM, Federoff HJ, Wüllner U, Papapetropoulos S, Youdim MB, Cantuti-Castelvetri I, Young AB, Vance JM, Davis RL, Hedreen JC, Adler CH, Beach TG, Graeber MB, Middleton FA, Rochet JC, Scherzer CR, & Global PD Gene Expression (GPEX) Consortium (2010). PGC-1?, a potential therapeutic target for early intervention in Parkinson’s disease. Science translational medicine, 2 (52) PMID: 20926834