The BDNF Val66Met polymorphism (rs6265) enhances dopamine neuron graft efficacy and side-effect liability in rs6265 knock-in rats.
The BDNF Val66Met polymorphism (rs6265) enhances dopamine neuron graft efficacy and side-effect liability in rs6265 knock-in rats.
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BDNF Val66Met 多态性 (rs6265) 增强 rs6265 敲入大鼠中的多巴胺神经元移植功效和副作用倾向。
DOI：
10.1016/j.nbd.2020.105175
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发表时间：
2021-01
影响因子：
6.1
通讯作者：
Steece-Collier K
中科院分区：
文献类型：
--
作者：
Mercado NM;Stancati JA;Sortwell CE;Mueller RL;Boezwinkle SA;Duffy MF;Fischer DL;Sandoval IM;Manfredsson FP;Collier TJ;Steece-Collier K
脑源性神经营养因子（BDNF）基因中的rs6265（也称为“Val 66 Met”）单核苷酸多态性（SNP）在全球约20%的人群中普遍存在，是一种常见的遗传变异，可以改变帕金森病（PD）患者的治疗反应。变体Met等位基因的拥有导致BDNF的活性依赖性释放减少。鉴于全球范围内对PD神经移植和BDNF生物学相关性的重新关注，目前的研究检查了rs6265 SNP对原发性多巴胺（DA）神经元移植后治疗疗效和副作用发展的影响。考虑到与rs6265相关的BDNF释放的显著减少，我们假设rs6265介导的功能障碍性BDNF信号传导有助于在PD患者亚群中观察到的有限的临床益处，尽管移植的DA神经元存活稳健，并且进一步地，该突变有助于异常移植物诱导的运动障碍（GID）的发展。为此，我们生成了rs6265 BDNF SNP的CRISPR敲入大鼠模型，以首次检查常见遗传多态性对移植物存活、功能功效和副作用倾向的影响，比较野生型（瓦尔/瓦尔）大鼠和变体Met等位基因（Met/Met）纯合大鼠之间的这些参数。与我们的假设相反，目前的研究表明，与野生型大鼠相比，Met/Met大鼠显示出增强的移植物相关治疗功效和移植物衍生的神经突生长的矛盾增强。然而，与我们的假设一致，我们证明宿主大鼠的rs6265基因型与GID的发展密切相关，并且这种行为表型与移植DA神经元的非典型多巴胺能神经传递的神经化学特征显著相关。
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.
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DOI：
10.1017/s1461145712000661
发表时间：
2013-03
期刊：
The international journal of neuropsychopharmacology
影响因子：
--
作者：
Bergman J;Roof RA;Furman CA;Conroy JL;Mello NK;Sibley DR;Skolnick P
通讯作者：
Skolnick P
影响因子：
5.3
作者：
Baydyuk M;Xu B
通讯作者：
Xu B
影响因子：
2.9
作者：
DUNNETT, SB;BJORKLUND, A;IVERSEN, SD
通讯作者：
IVERSEN, SD
影响因子：
8.6
作者：
Collier, Timothy J.;Sortwell, Caryl E.;Steece-Collier, Kathy
通讯作者：
Steece-Collier, Kathy
影响因子：
4.2
作者：
Di Pino, Giovanni;Pellegrino, Giovanni;Di Lazzaro, Vincenzo
通讯作者：
Di Lazzaro, Vincenzo