The proSAAS Chaperone Provides Neuroprotection and Attenuates Transsynaptic α-Synuclein Spread in Rodent Models of Parkinson's Disease.
The proSAAS Chaperone Provides Neuroprotection and Attenuates Transsynaptic α-Synuclein Spread in Rodent Models of Parkinson's Disease.
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DOI：
10.3233/jpd-213053
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发表时间：
2022
影响因子：
5.2
通讯作者：
Maidment, Nigel T.
中科院分区：
文献类型：
--
作者：
Lindberg, Iris;Shu, Zhan;Lam, Hoa;Helwig, Michael;Yucer, Nur;Laperle, Alexander;Svendsen, Clive N.;Di Monte, Donato A.;Maidment, Nigel T.
帕金森病涉及突触蛋白-突触核蛋白（aSyn）在黑质纹状体束中的异常聚集。我们之前已经证明，proSAAS，一种小的神经元伴侣，在原代培养中阻断了asynn诱导的多巴胺能细胞毒性。确定proSAAS过表达是否对帕金森病动物模型具有神经保护作用。将编码ProSAAS或gfp的慢病毒与人类表达异步的AAV一起单侧注射到大鼠的黑质中，并通过一系列运动性能测试评估运动不对称性。采用神经立体学和纹状体酪氨酸羟化酶（TH）密度测定法评估多巴胺神经元存活。为了检测aSyn的跨突触传播，在编码GFP或proSAAS的AAV存在的情况下，将aSyn AAV注入小鼠迷走神经；采用免疫组化方法定量观察非阳性神经突向吻侧核的扩散情况。共注射编码prosaas的慢病毒可显著降低单侧黑质aav介导的人aSyn过表达引起的运动不对称性。与此同时，人类异步诱导的黑质纹状体th阳性细胞和纹状体th阳性终末的损失显著改善，表明prosaas介导的黑质纹状体束保护作用明显。ProSAAS过表达降低了人黑质和纹状体中的aSyn蛋白水平，并减少了这两个区域中TH蛋白的损失。迷走神经给药后，共注射proSAAS-而非gfp -编码AAV的小鼠脑桥和尾侧中脑的人源性异步阳性神经突数量显著减少，支持proSAAS介导的跨突触异步传递阻断。proSAAS伴侣可能是帕金森病治疗发展的一个有希望的靶点。
Parkinson’s disease involves aberrant aggregation of the synaptic protein alpha synuclein (aSyn) in the nigrostriatal tract. We have previously shown that proSAAS, a small neuronal chaperone, blocks aSyn-induced dopaminergic cytotoxicity in primary nigral cultures. To determine if proSAAS overexpression is neuroprotective in animal models of Parkinson’s disease. ProSAAS- or GFP-encoding lentivirus was injected together with human aSyn-expressing AAV unilaterally into the substantia nigra of rats and motor asymmetry assessed using a battery of motor performance tests. Dopamine neuron survival was assessed by nigral stereology and striatal tyrosine hydroxylase (TH) densitometry. To examine transsynaptic spread of aSyn, aSyn AAV was injected into the vagus of mice in the presence of AAVs encoding either GFP or proSAAS; the spread of aSyn-positive neurites into rostral nuclei was quantified following immunohistochemistry. Coinjection of proSAAS-encoding lentivirus profoundly reduced the motor asymmetry caused by unilateral nigral AAV-mediated human aSyn overexpression. This was accompanied by significant amelioration of the human aSyn-induced loss of both nigral TH-positive cells and striatal TH-positive terminals, demonstrating clear proSAAS-mediated protection of the nigrostriatal tract. ProSAAS overexpression reduced human aSyn protein levels in nigra and striatum, and reduced the loss of TH protein in both regions. Following vagal administration of human aSyn-encoding AAV, the number of human aSyn-positive neurites in the pons and caudal midbrain was considerably reduced in mice coinjected with proSAAS-, but not GFP-encoding AAV, supporting proSAAS-mediated blockade of transsynaptic aSyn transmission. The proSAAS chaperone may represent a promising target for therapeutic development in Parkinson’s disease.