The BDNF Val66Met polymorphism (rs6265) enhances dopamine neuron graft efficacy and side-effect liability in rs6265 knock-in rats

Natosha M. Mercado, Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA.
Jennifer A. Stancati, Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA.
Caryl E. Sortwell, Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA; Hauenstein Neuroscience Center, Mercy Health Saint Mary's, Grand Rapids, Michigan 49503, USA.
Rebecca L. Mueller, Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA.
Samuel A. Boezwinkle, College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, Michigan 48109, USA.
Megan F. Duffy, Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA.
D Luke Fischer, Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA.
Ivette M. Sandoval, Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA; Hauenstein Neuroscience Center, Mercy Health Saint Mary's, Grand Rapids, Michigan 49503, USA.
Fredric P. Manfredsson, Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA; Hauenstein Neuroscience Center, Mercy Health Saint Mary's, Grand Rapids, Michigan 49503, USA.Follow
Timothy J. Collier, Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA; Hauenstein Neuroscience Center, Mercy Health Saint Mary's, Grand Rapids, Michigan 49503, USA.
Kathy Steece-Collier, Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA; Hauenstein Neuroscience Center, Mercy Health Saint Mary's, Grand Rapids, Michigan 49503, USA. Electronic address: collie68@msu.edu.

Document Type

Article

Abstract

Prevalent in approximately 20% of the worldwide human population, the rs6265 (also called 'Val66Met') single nucleotide polymorphism (SNP) in the gene for brain-derived neurotrophic factor (BDNF) is a common genetic variant that can alter therapeutic responses in individuals with Parkinson's disease (PD). Possession of the variant Met allele results in decreased activity-dependent release of BDNF. Given the resurgent worldwide interest in neural transplantation for PD and the biological relevance of BDNF, the current studies examined the effects of the rs6265 SNP on therapeutic efficacy and side-effect development following primary dopamine (DA) neuron transplantation. Considering the significant reduction in BDNF release associated with rs6265, we hypothesized that rs6265-mediated dysfunctional BDNF signaling contributes to the limited clinical benefit observed in a subpopulation of PD patients despite robust survival of grafted DA neurons, and further, that this mutation contributes to the development of aberrant graft-induced dyskinesias (GID). To this end, we generated a CRISPR knock-in rat model of the rs6265 BDNF SNP to examine for the first time the influence of a common genetic polymorphism on graft survival, functional efficacy, and side-effect liability, comparing these parameters between wild-type (Val/Val) rats and those homozygous for the variant Met allele (Met/Met). Counter to our hypothesis, the current research indicates that Met/Met rats show enhanced graft-associated therapeutic efficacy and a paradoxical enhancement of graft-derived neurite outgrowth compared to wild-type rats. However, consistent with our hypothesis, we demonstrate that the rs6265 genotype in the host rat is strongly linked to development of GID, and that this behavioral phenotype is significantly correlated with neurochemical signatures of atypical glutamatergic neurotransmission by grafted DA neurons.

Keywords

BDNF, Neural grafting, Parkinson’s disease, Val66Met, Val68Met, rs6265

Medical Subject Headings

Animals; Antiparkinson Agents (adverse effects); Brain-Derived Neurotrophic Factor (genetics); Cell Transplantation (adverse effects, methods); Dopaminergic Neurons (metabolism, transplantation); Dyskinesia, Drug-Induced (etiology); Dyskinesias (etiology, genetics); Embryo, Mammalian; Gene Knock-In Techniques; Levodopa (adverse effects); Mesencephalon (cytology); Oxidopamine (toxicity); Parkinson Disease, Secondary (chemically induced); Rats; Sympatholytics (toxicity); Vesicular Glutamate Transport Protein 2 (metabolism)

Publication Date

1-1-2021

Publication Title

Neurobiology of disease

E-ISSN

1095-953X

Volume

148

First Page

105175

PubMed ID

33188920

Digital Object Identifier (DOI)

10.1016/j.nbd.2020.105175

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