Finding an Optimal Level of GDNF Overexpression: Insights from Dopamine Cycling

The application of glial cell line-derive neurotrophic factor (GDNF) to cell cultures and animal models has demonstrated positive effects upon dopaminergic neuronal survival and development, function, restoration, and protection. On this basis, recombinant GDNF protein has been trialled in the treatment of late-stage human Parkinson's disease patients with only limited success that is likely due to a lack of viable receptor targets in an advanced state of neurodegeneration. The latest research points to more refined approaches of modulating GDNF signalling and an optimal quantity and spatial regulation of GDNF can be extrapolated using regulation of dopamine as a proxy measure. The basic research literature on dopaminergic effects of GDNF in animal models is reviewed, concluding that a twofold increase in natively expressing cells increases dopamine turnover and maximises neuroprotective and beneficial motor effects whilst minimising hyperdopaminergia and other side-effects. Methodological considerations for measurement of dopamine levels and neuroanatomical distinctions are made between populations of dopamine neurons and their respective effects upon movement and behaviour that will inform future research into this still-relevant growth factor. [GRAPHICS]

Automated summary

The application of glial cell line-derived neurotrophic factor (GDNF) has shown positive effects on the survival, development, function, restoration, and protection of dopaminergic neurons in cell cultures and animal models. However, trials using recombinant GDNF protein in late-stage Parkinson's disease patients have had limited success, possibly due to a lack of viable receptor targets in advanced neurodegeneration. Recent research suggests refined approaches to modulating GDNF signaling and using dopamine regulation as a proxy measure for optimal quantity and spatial regulation of GDNF. Basic research on the dopaminergic effects of GDNF in animal models concludes that increasing the number of natively expressing cells can enhance dopamine turnover and maximize neuroprotective and beneficial motor effects while minimizing hyperdopaminergia and side effects. Methodological considerations for measuring dopamine levels and understanding neuroanatomical distinctions will inform future research on this relevant growth factor.