Exploring GFRα-1 as a potential therapeutic target for preventing tyrosine hydroxylase loss in an experimental Parkinson’s Disease model

Background: Parkinson’s disease (PD) is the most common neurodegenerative movement disorder. Glial cell-line derived neurotrophic factor (GDNF) increases dopamine neuron function in vitro and in vivo in rodent models, making it a promising candidate for the treatment of PD. In fact, unilateral delivery of GDNF increased locomotor function bilaterally in two of three PD clinical trails. Lack of improvement in a subsequent clinical trial has halted further clinical work. Thus, evaluating downstream impact of GDNF may identify additional targets to improve locomotor impairment in the PD patient. Hypothesis: Striatal GDNF infusion increases expression of GFRα-1 and tyrosine hydroxylase (TH) phosphorylation in the substantia nigra (SN) of aged rats 4 weeks after GDNF delivery. Here we tested the hypothesis that GDNF may produce a bilateral increase in GFRα-1 expression in the striatum & SN, between one and four weeks after striatal delivery. We further hypothesized that the long-lasting effect of GDNF on dopamine and TH may be related to sustained expression of GFRα-1, and therefore determined if GFRα-1 could be protective against loss of TH and dopamine caused by 6-hydroxydopamine (6-OHDA) lesion. We used a rat model of PD to address this question. Methods: Part 1. To test whether unilateral GDNF could increase GFRα-1 bilaterally, GDNF (30 µg) was delivered unilaterally into the dorsal striatum of 24-month old Brown-Norway Fischer 344 F1 male rats. Striatal and SN tissue samples were bilaterally dissected at one day, one week, and four-week time intervals after GDNF infusion. Part 2. To determine if GFRα-1 alone could protect against 6-OHDA lesion, GFRα-1 was infused into either striatum or SN via guide cannula 6 days following lesion. Dopamine and TH expression were determined 4 days later. Results: Part 1. GDNF increased in GFR-α1 expression bilaterally in the striatum and SN four weeks following GDNF compared to 1 week expression levels. Part 2. GFR-α1 (1 ng) delivered into the SN produced a significant reduction in both dopamine and TH protein loss caused by 6-OHDA that was selective for the SN. However, GFR-α1 delivery into the striatum did not produce any reduction in either dopamine or TH loss. Conclusions: Increased GFR-α1 expression in the SN may be associated with the previously observed effects of GDNF upon locomotor function via expression of TH and increased dopamine content in the SN alone.