Boosting the body’s own production of neurotrophic factors could help Parkinson's sufferers

A recent study indicates that GDNF clearly regulates the function of the dopaminergic neurons in the midbrain. With the help of a new research method, the amount of GDNF was topically increased specifically in the areas of the brain associated with GDNF production, such as the areas which are central to the development of Parkinson's disease.

The motor symptoms of Parkinson’s result from the gradual loss of function and subsequent destruction of dopaminergic neurons in the midbrain. GDNF-based therapy has been one of the most promising treatments for Parkinson’s. In animal models, GDNF injected directly into the head has effectively protected dopaminergic neurons from experimental damage, and even repaired existing damage.

The efficacy of GDNF has also been tested on Parkinson’s sufferers, but despite initial promising results, extensive benefit was not conclusively established in the two second-stage clinical studies so far conducted.

“The modest results are likely at least partially attributable to problems with dosage and delivery. GDNF is a large protein, so introducing it directly into brain tissue is difficult, and can result in uncontrolled neurite outgrowth at the injection site.  Further information is also needed on the mechanisms through which GDNF influences the dopaminergic neurons, particularly in the ageing brain,” states Jaan-Olle Andressoo, principal investigator at the University of Helsinki’s Institute of Biotechnology.

 

Controlled release of GDNF possible

Jaan-Olle Andressoo has developed a new microRNA-based method for increasing the amount of GDNF in the brain.

“The benefit of the resulting mouse model is that the amount of GDNF is increased in a controlled manner and only in the cells that normally express it. In the part of the brain most crucial for Parkinson's disease, the striatum, the expression of GDNF was doubled. In addition, the expression remains susceptible to normal gene regulation. This means we can gain information on the physiological effects of GDNF, which was not possible with previous methods,” Jaan-Olle Andressoo explains.

In follow-up studies conducted at the University of Helsinki's Faculty of Pharmacy, the overexpression of GDNF was found to slightly increase the number of dopaminergic neurons as well as the amount of dopamine in the striatum. The overexpression also enhanced the release of dopamine and protected the neurons from damage.

The impact on Parkinson’s disease was studied together with Professor Mart Saarma. Researchers from Umeå University and the University of Tartu also participated in studying GDNF’s mechanisms of action.

Based on the research results, principal investigator Jaan-Olle Andressoo is now developing methods which would enable the increase bodies own GDNF levels inside the brain.

“If we succeed, we will probably be able to restore neural connections that have already been weakened using specific elevation of bodies own neurotrophic factors, first among Parkinson’s sufferers, and later among patients with other degenerative neural illnesses. Our preliminary results are highly promising,” suggests Andressoo.