ProSAAS 伴侣蛋白可提供神经保护作用，并减轻帕金森病啮齿动物模型中的突触间 α-突触核蛋白传播。
The proSAAS Chaperone Provides Neuroprotection and Attenuates Transsynaptic α-Synuclein Spread in Rodent Models of Parkinson's Disease.
机构信息
University of Maryland-Baltimore, Baltimore, MD, USA.
University of California at Los Angeles, Los Angeles, CA, USA.
出版信息
J Parkinsons Dis. 2022;12(5):1463-1478. doi: 10.3233/JPD-213053.
BACKGROUND
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.
OBJECTIVE
To determine if proSAAS overexpression is neuroprotective in animal models of Parkinson's disease.
METHODS
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.
RESULTS
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.
CONCLUSION
The proSAAS chaperone may represent a promising target for therapeutic development in Parkinson's disease.
背景
帕金森病涉及突触蛋白α-突触核蛋白（aSyn）在黑质纹状体束中的异常聚集。我们之前已经表明，小神经元伴侣 proSAAS 可阻断原代黑质培养物中 aSyn 诱导的多巴胺能细胞毒性。
目的
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。
方法
将 proSAAS 或 GFP 编码慢病毒与表达人 aSyn 的 AAV 单侧共注射到大鼠黑质中，并使用一系列运动表现测试评估运动不对称。通过黑质立体学和纹状体酪氨酸羟化酶（TH）密度测定评估多巴胺神经元存活。为了检查 aSyn 的跨突触传播，在注射编码 GFP 或 proSAAS 的 AAV 的同时将 aSyn AAV 注射到小鼠的迷走神经中；通过免疫组织化学定量分析 aSyn 阳性神经突进入前脑核的传播。
结果
共注射 proSAAS 编码慢病毒可显著减少单侧黑质 AAV 介导的人 aSyn 过表达引起的运动不对称。这伴随着人 aSyn 诱导的黑质 TH 阳性细胞和纹状体 TH 阳性终末的明显改善，表明 proSAAS 介导的黑质纹状体束的明显保护作用。proSAAS 过表达降低了黑质和纹状体中人 aSyn 蛋白水平，并减少了两个区域中 TH 蛋白的丢失。在迷走神经给予人 aSyn 编码 AAV 后，在共注射 proSAAS 而不是 GFP 编码 AAV 的小鼠中，桥脑和中脑尾部的人 aSyn 阳性神经突数量大大减少，支持 proSAAS 介导的跨突触 aSyn 传递阻断。
结论
proSAAS 伴侣可能是帕金森病治疗开发的有希望的靶点。
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