Objective: To determine if GDNF receptor expression levels in the striatum or substantia nigra (SN) change in relation to differences in tyrosine hydroxylase (TH) and TH phosphorylation during progressive nigrostriatal neuron loss.

Background: Preclinical and the first clinical trials using GDNF in Parkinson’s disease (PD) showed efficacy to mitigate parkinsonian signs in PD animal models and in moderate stage PD patients.  However, subsequent placebo-controlled trials did not meet primary endpoints.  These study outcomes have not only given pause to pursue further investigation in patients, but have obscured the original findings of GDNF-related benefits in patients. We investigate the possibility that diminished of expression of GDNF family receptor, GFR-α1, or GDNF receptor tyrosine kinase, RET, may play a role in the failure of GDNF in clinical trials.

Method: Using a hemi-parkinsonian 6-OHDA rat model, we evaluated expression of GFR-α1 and RET in striatum and SN at 1 and 4 weeks following a 6-hydroxydopamine (6-OHDA) lesion.  We also determined if BDNF and TrkB receptor expression changed alongside any changes in the GDNF receptors.

Results: GFR-α1 expression decreased progressively in striatum and in tyrosine hydroxylase positive (TH+) neurons in SN, with strong correlation with progressive reductions in TH+ neurons.  RET expression decreased maximally in striatum by 1 week, whereas in the SN, there was a bilateral increase 7 days after lesion that receded to levels in the sham-operation group by 4 weeks.  Expression of BDNF or its receptor, TrkB, were unchanged throughout lesion progression.  TH phosphorylation at ser31 decreased in striatum, but was consistently increased in SN throughout lesion progression, suggesting RET expression may be a critical upstream component in ser31 TH phosphorylation and thus, maintain dopamine (DA) synthesis capacity in the SN during neuronal loss.

Conclusion: Since the timing of GDNF intervention in PD patients began at least 5 years after diagnosis (a time point reflecting virtual complete loss of nigrostriatal DA markers), our study shows that limited efficacy of GDNF may be explained by greatly diminished GDNF receptor expression in striatum.  Strategies that increase GFR-α1 and RET may prove more efficacious than GDNF to augment TH expression and DA synthesis capacity.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/are-gdnf-receptors-the-gatekeepers-of-gdnf-efficacy-during-progressive-nigrostriatal-neuron-loss/