Mechanisms of Enhanced Neuroregeneration Associated with the Common Human Single Nucleotide Polymorphism Val66Met
Abstract
Mechanisms underlying graft-induced dyskinesia (GID), a cell replacement side effect that can occur in individuals with Parkinson's disease (PD), remain unknown and controversial. As a potential genetic contribution to this therapeutic outcome, our lab focuses on a common single nucleotide polymorphism (SNP), rs6265, found in the gene for brain-derived neurotrophic factor (BDNF) resulting in decreased BDNF release. Using rs6265 knock-in rats, we previously demonstrated that homozygous rs6265 (Met/Met) parkinsonian rats engrafted with wild-type (WT; Val/Val) dopamine (DA) neurons uniquely developed GID. This behavioral phenotype was correlated with neurochemical signatures of immature DA-glutamate co-transmission normally seen during development. Based on the necessity of BDNF for DA neuron maturation, we hypothesize that decreased BDNF release in rs6265-carriers impairs maturation and synaptogenesis of grafted DA neurons, leading to GID, and that infusion of exogenous BDNF will allow for graft maturation, normalization of graft-derived synaptic innervation, and GID prevention. To test this hypothesis, male parkinsonian Met/Met rats were transplanted with intrastriatal embryonic WT DA neurons. Infusion cannulas were stereotaxically inserted 3 mu m dorsal to grafted cells at time of grafting and attached to 28-day Alzet (trademark) osmotic minipumps containing BDNF or vehicle phosphate buffered saline (PBS). Pumps were removed after four weeks. Levodopa-induced dyskinesia (LID) and GID severity were evaluated over 10 weeks post-engraftment. DA-grafted animals infused with PBS or BDNF exhibited significant amelioration of LID compared to non-grafted animals, demonstrating successful engraftment. Contrary to our hypothesis, BDNF infusion in grafted animals increased amphetamine- and levodopa-mediated GID behavior in Met/Met hosts.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2023
- Accession Number
- AD1225072
Entities
People
- C. Szarowicz
- Kathy Steece-collier
- Margaret Caulfield
Organizations
- Michigan State University