Objective: Extend investigations into the effect of the rs6265 single nucleotide polymorphism (SNP) on dopamine (DA) neuron graft efficacy using a parkinsonian rat model.

Background: rs6265 (aka: Val66Met) is a common human SNP in the gene for brain-derived neurotrophic factor (BDNF) resulting in decreased release. Based on the importance of BDNF in neural development and DA grafting, we hypothesized that decreased BDNF associated with rs6265 would impair synaptogenesis of grafted DA neurons resulting in suboptimal efficacy and aberrant graft-induced dyskinesias (GID). Using CRISPR knock-in rats, we recently reported that rats homozygous for the Met risk allele (Met/Met; M/M) engrafted with embryonic DA neurons from wild-type (WT; Val/Val) donors showed paradoxical enhancement of graft function compared to WT rats¹. The Met allele was also uniquely associated with GID¹. To expand our understanding of the influence of rs6265 in DA graft outcome, we are examining the impact of rs6265 in the host and/or donor.

Method: WT and M/M rats were rendered unilaterally parkinsonian, evaluated for amphetamine rotations and levodopa-induced dyskinesias, our primary and secondary measures of graft function; assessed over 10 wks post-engraftment. WT and M/M rats received E14 ventral mesencephalic cells from WT or M/M donors providing six host-donor combinations: WT-Sham (N=7); M/M-Sham (N=8); WT-WT (N=8); M/M-M/M (N=9);M/M-WT (N=8); WT-M/M (N=8).

Results: Our findings indicate that the rs6265 Met allele in the host promotes efficacy but induces GID side-effects¹. Additional influences of rs6265 in donor and/or host are pending. The rs6265 SNP is in the BDNF pro-domain/pro-peptide. The dramatic benefit of this genetic variation in grafting¹ and traumatic brain injury^2,3 suggests an important role for the Met pro-peptide in neuroregeneration. We anticipate that in rs6265 Met allele carriers (host or donor), the variant BDNF pro-peptide will promote neurite outgrowth, but that diminished levels of mature BDNF in the rs6265 graft environment will prevent graft maturation and induce GID.

Conclusion: The role of specific genetic variations in the success of neural grafting for individuals with Parkinson’s disease (PD) has been entirely unexplored. In an era of precision medicine, understanding the influence of one’s genotype will doubtless aid in the development of safe, optimized treatments for PD.

References: 1. Mercado, N.M., et al., The BDNF Val66Met polymorphism (rs6265) enhances dopamine neuron graft efficacy and side-effect liability in rs6265 knock-in rats. Neurobiol Dis, 2021. 148: p. 105175.
2. Failla, M.D., et al., Variation in the BDNF gene interacts with age to predict mortality in a prospective, longitudinal cohort with severe TBI. Neurorehabil Neural Repair, 2015. 29(3): p. 234-46.
3. Krueger, F., et al., The role of the Met66 brain-derived neurotrophic factor allele in the recovery of executive functioning after combat-related traumatic brain injury. J Neurosci, 2011. 31(2): p. 598-606.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/impact-of-rs6265-in-the-host-and-donor-on-dopamine-neuron-graft-function/