Abstract Title

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

RAD Assignment Number

1518

Presenter Name

Christopher Tan

Abstract

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.

Presentation Type

Poster

This document is currently not available here.

Share

COinS
 

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.