Glial cell line-derived neurotrophic factor and Parkinson's disease: Is its family receptor the missing link?

Purpose: Glial cell line-derived neurotrophic factor (GDNF) improved motor function in Parkinson's disease (PD) preclinical and Phase I trials whereas mixed results were generated for Phase II trials. This disparity in outcome may be attributed to several factors including disease severity at treatment onset. Although GDNF is delivered to the striatum, increasing reports suggest that its recovery in the substantia nigra (SN) is vital for motor recovery, a process which may be compromised with PD progression. GDNF delivery in aged rats, wherein bradykinesia is evident, induces expression of its family receptor, GFR-ɑ1, in the SN. Indeed, replenishment of GFR-ɑ1, which is decreased in the SN in aged models, improves motor function, suggesting that GFR-ɑ1 may be critical for motor benefits. Using a hemi-Parkinson's model wherein bradykinesia is also evident, we evaluated for changes in GFR-ɑ1 expression with lesion progression. Method: 3-month old male Sprague-Dawley rats were euthanized on days 7 and 28 post-lesion induction for neurochemical assays. Results: A lesion-associated decline in GFR-ɑ1 protein expression was observed in the striatum at both time points. Also, there was a more significant reduction in the 28-day versus 7-day cohort denoting a progressive loss of GFR-ɑ1. Conclusion: These results suggest that GFR-ɑ1 in the striatum declines with nigrostriatal dysfunction progression and thus, may be a limiting factor in GDNF efficacy. Maintaining GFR-ɑ1 expression in the striatum may therefore be a link in the restorative capacity of GDNF.