Your browser doesn't support javascript.
loading
The BDNF Val66Met polymorphism (rs6265) enhances dopamine neuron graft efficacy and side-effect liability in rs6265 knock-in rats.
Mercado, Natosha M; Stancati, Jennifer A; Sortwell, Caryl E; Mueller, Rebecca L; Boezwinkle, Samuel A; Duffy, Megan F; Fischer, D Luke; Sandoval, Ivette M; Manfredsson, Fredric P; Collier, Timothy J; Steece-Collier, Kathy.
Afiliación
  • Mercado NM; Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA.
  • Stancati JA; Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA.
  • Sortwell CE; 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.
  • Mueller RL; Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA.
  • Boezwinkle SA; College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, Michigan 48109, USA.
  • Duffy MF; Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA.
  • Fischer DL; Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA.
  • Sandoval IM; 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.
  • Manfredsson FP; 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.
  • Collier TJ; 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.
  • Steece-Collier K; 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.
Neurobiol Dis ; 148: 105175, 2021 01.
Article en En | MEDLINE | ID: mdl-33188920
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.
Asunto(s)
Palabras clave
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Trasplante de Células / Factor Neurotrófico Derivado del Encéfalo / Discinesias / Neuronas Dopaminérgicas Tipo de estudio: Etiology_studies / Prognostic_studies Límite: Animals Idioma: En Revista: Neurobiol Dis Asunto de la revista: NEUROLOGIA Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Trasplante de Células / Factor Neurotrófico Derivado del Encéfalo / Discinesias / Neuronas Dopaminérgicas Tipo de estudio: Etiology_studies / Prognostic_studies Límite: Animals Idioma: En Revista: Neurobiol Dis Asunto de la revista: NEUROLOGIA Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos