The death of dopaminergic neurons in the substantia nigra is a major pathology underlying Parkinson’s disease. Therefore it makes a lot of sense to look to neurotrophic factors, the most potent mediators of neuronal survival identified to date, as promising therapeutic agents for saving these neurons. A new review paper “Repairing the parkinsonian brain with neurotrophic factors” (published February 2011 in Trends in Neurosciences) states that, so far, clinical trials of neurotrophic factors to treat Parkinson’s disease have been disappointing. Why?

Figure 1. An overview of glial cell line-derived neurotrophic factor (GDNF) signaling. Figure 1 from “Repairing the parkinsonian brain with neurotrophic factors” by Liviu Aron and Rudiger Klein. Trends in Neurosciences, February 2011.

Details of molecular signal pathways are known for some neurotrophic factors. For example, one can follow the glial cell line-derived neurotrophic factor (GDNF) signal step-by-step (see Figure 1 above; for text describing the figure please see the review paper). Nevertheless, even for GDNF, the outcomes of the interactions are poorly understood and it remains to be determined what interactions actually promote survival of dopaminergic neurons. The authors of the review conclude that we simply do not know enough yet about how neurotrophic factors work.

The authors state that “the experimental evidence that neurotrophic factor disturbances alone cause Parkinson’s disease is currently weak.” Nevertheless, they cite the following to encourage continued research in this area:

• Parkinson’s disease-associated genes require an intact neurotrophic factor network to promote substantia nigra neuron survival during aging.
• Changes induced by mutations in Parkinson’s disease-associated genes decrease the efficacy of neurotrophic factor signaling.
• Shared substrates between neurotrophic factors and Parkinson’s disease-associated proteins might represent new targets for drug development in Parkinson’s disease.

Certainly research in neurotrophic factors and Parkinson’s disease must continue to move forward. Interestingly there were two sentences in the review’s conclusion that seemed tacked on and were not discussed:

• The creation of a common database with results from standardized experiments could result in a systems biology approach in experimental Parkinson’s disease.
• Mathematical models of neurotrophic factor action could then be used to predict and test new cellular targets.

Creating a common database and associated systems biology models may accelerate the field by enabling a broad set of scientists to understand the complex signaling pathways underlying neurotrophic factor function and the way they may be applied to helping Parkinson’s disease patients.