Novel mechanism and genetic association of graft-induced dyskinesia in CRISPR rs6265 BDNF polymorphism rats
Year: 2026
Type: article
Abstract: Dopamine (DA) cell replacement remains a promising therapeutic for Parkinson’s disease; however, mechanisms underlying graft-induced dyskinesias (GID) remain unclear/controversial. To understand potential genetic contributions, we have been investigating a single nucleotide polymorphism, rs6265, found in the brain-derived neurotrophic factor (BDNF) gene, which results in decreased BDNF release. Using a CRISPR knock-in rat model, we first reported that parkinsonian rs6265 rats engrafted with wild-type (WT) primary DA neurons uniquely developed GID compared to WT counterparts. Based on its importance for DA neuron maturation/function, we hypothesized that “replenishing” BDNF in rs6265-carriers would ameliorate GID. Unexpectedly, BDNF supplementation exacerbated GID, with evidence suggesting that a maintained immature DA/glutamate co-expression phenotype and/or excess DA release through a novel mechanism, vesicular synergy, contributes to GID expression. Our findings are supported by clinical data and reveal novel mechanisms related to an individual’s genetic profile that may be important to consider in ongoing cell transplantation clinical trials.
Source: npj Parkinson s Disease
Institution: Michigan State University
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,890
OpenAlex ID: W7225398063