Sorrentino Zachary A, Brooks Mieu M T, Hudson Vincent, Rutherford Nicola J, Golde Todd E, Giasson Benoit I, Chakrabarty Paramita
Department of Neuroscience, University of Florida, 1275 Center Drive, PO Box 100159, Gainesville, FL, 32610, USA.
Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, 32610, USA.
Mol Neurodegener. 2017 May 29;12(1):40. doi: 10.1186/s13024-017-0182-z.
Prionoid transmission of α-synuclein (αSyn) aggregates along neuroanatomically connected projections is posited to underlie disease progression in α-synucleinopathies. Here, we specifically wanted to study whether this prionoid progression occurs via direct inter-neuronal transfer and, if so, would intrastriatal injection of αSyn aggregates lead to nigral degeneration.
To test prionoid transmission of αSyn aggregates along the nigro-striatal pathway, we injected amyloidogenic αSyn aggregates into two different regions of the striatum of adult human wild type αSyn transgenic mice (Line M20) or non-transgenic (NTG) mice and aged for 4 months.
M20 mice injected in internal capsule (IC) or caudate putamen (CPu) regions of the striatum showed florid αSyn inclusion pathology distributed throughout the neuraxis, irrespective of anatomic connectivity. These αSyn inclusions were found in different cell types including neurons, astrocytes and even ependymal cells. On the other hand, intra-striatal injection of αSyn fibrils into NTG mice resulted in sparse αSyn pathology, mostly localized in the striatum and entorhinal cortex. Interestingly, NTG mice injected with preformed human αSyn fibrils showed no induction of αSyn inclusion pathology, suggesting the presence of a species barrier for αSyn fibrillar seeds. Modest levels of nigral dopaminergic (DA) neuronal loss was observed exclusively in substantia nigra (SN) of M20 cohorts injected in the IC, even in the absence of frank αSyn inclusions in DA neurons. None of the NTG mice or CPu-injected M20 mice showed DA neurodegeneration. Interestingly, the pattern and distribution of induced αSyn pathology corresponded with neuroinflammation especially in the SN of M20 cohorts. Hypermorphic reactive astrocytes laden with αSyn inclusions were abundantly present in the brains of M20 mice.
Overall, our findings show that the pattern and extent of dissemination of αSyn pathology does not necessarily follow expected neuroanatomic connectivity. Further, the presence of intra-astrocytic αSyn pathology implies that glial cells participate in αSyn transmission and possibly have a role in non-cell autonomous disease modification.
α-突触核蛋白（αSyn）聚集体沿神经解剖学连接的投射进行类朊病毒传播被认为是α-突触核蛋白病疾病进展的基础。在此，我们特别想研究这种类朊病毒进展是否通过神经元间的直接转移发生，如果是这样，纹状体内注射αSyn聚集体是否会导致黑质变性。
为了测试αSyn聚集体沿黑质-纹状体通路的类朊病毒传播，我们将淀粉样生成性αSyn聚集体注射到成年人类野生型αSyn转基因小鼠（M20系）或非转基因（NTG）小鼠纹状体的两个不同区域，并饲养4个月。
在纹状体的内囊（IC）或尾状核壳（CPu）区域注射的M20小鼠显示出遍布神经轴的明显αSyn包涵体病理，与解剖学连接无关。这些αSyn包涵体存在于不同细胞类型中，包括神经元、星形胶质细胞甚至室管膜细胞。另一方面，向NTG小鼠纹状体内注射αSyn纤维导致稀疏的αSyn病理，主要局限于纹状体和内嗅皮质。有趣的是，注射了预先形成的人类αSyn纤维的NTG小鼠未出现αSyn包涵体病理的诱导，这表明αSyn纤维种子存在物种屏障。仅在IC注射的M20组的黑质（SN）中观察到适度水平的黑质多巴胺能（DA）神经元丢失，即使DA神经元中没有明显的αSyn包涵体。NTG小鼠或CPu注射的M20小鼠均未显示DA神经变性。有趣的是，诱导的αSyn病理的模式和分布与神经炎症相对应，尤其是在M20组的SN中。充满αSyn包涵体的高反应性星形胶质细胞大量存在于M20小鼠的大脑中。
总体而言，我们的研究结果表明，αSyn病理的传播模式和程度不一定遵循预期的神经解剖学连接。此外，星形胶质细胞内αSyn病理的存在意味着胶质细胞参与αSyn传播，并且可能在非细胞自主性疾病修饰中起作用。
