■广泛存在的皮质突触核蛋白病是潜在临床实体的主要神经病理学标志,如帕金森病伴痴呆(PDD)和路易体痴呆(DLB)。目前迫切需要开发PDD和DLB的非人灵长类动物(NHP)模型以进一步克服药物发现中的现有限制。
■在这里,我们利用了编码α-突触核蛋白A53T突变基因(AAV9-SynA53T)的逆行扩散的腺相关病毒载体血清型9诱导了皮质和皮质下神经支配壳核的广泛突触核蛋白病。AAV分娩后四周处死动物,并进行全面的生物分布研究。包括表达α-突触核蛋白的神经元的定量,rostrocaudaldistributionandtheirspecificlocation.
■AAV9-SynA53T的肌内分娩导致整个同侧和对侧大脑皮质的播散性突触核蛋白病,连同位于同侧尾侧膜内核和黑质致密质中的转导神经元(导致丘脑纹状体和黑质纹状体投射,分别)。皮层传入系统被发现是质核传入(特别是额叶上和中央前回旋)的主要贡献者。
■获得的数据扩展了NHP中突触核蛋白病的当前模型,提供了一个可重复的平台,能够充分实施针对α-突触核蛋白的新药的终末期临床前筛选。
UNASSIGNED: The presence of a widespread cortical synucleinopathy is the main neuropathological hallmark underlying clinical entities such as Parkinson\'s disease with dementia (PDD) and dementia with Lewy bodies (DLB). There currently is a pressing need for the development of non-human primate (NHPs) models of PDD and DLB to further overcome existing limitations in drug discovery.
UNASSIGNED: Here we took advantage of a retrogradely-spreading adeno-associated viral vector serotype 9 coding for the alpha-synuclein A53T mutated gene (AAV9-SynA53T) to induce a widespread synucleinopathy of cortical and subcortical territories innervating the putamen. Four weeks post-AAV deliveries animals were sacrificed and a comprehensive biodistribution study was conducted, comprising the quantification of neurons expressing alpha-synuclein, rostrocaudal distribution and their specific location.
UNASSIGNED: Intraputaminal deliveries of AAV9-SynA53T lead to a disseminated synucleinopathy throughout ipsi- and contralateral cerebral cortices, together with transduced neurons located in the ipsilateral caudal intralaminar nuclei and in the substantia nigra pars compacta (leading to thalamostriatal and nigrostriatal projections, respectively). Cortical afferent systems were found to be the main contributors to putaminal afferents (superior frontal and precentral gyri in particular).
UNASSIGNED: Obtained data extends current models of synucleinopathies in NHPs, providing a reproducible platform enabling the adequate implementation of end-stage preclinical screening of new drugs targeting alpha-synuclein.