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CSF-derived extracellular vesicles from patients with Parkinson's disease induce symptoms and pathology
Brain ( IF 14.5 ) Pub Date : 2022-07-26 , DOI: 10.1093/brain/awac261
Shay Herman 1 , Ruth Djaldetti 2, 3 , Brit Mollenhauer 4, 5 , Daniel Offen 1, 6
Affiliation  

Parkinson’s disease is characterized by the gradual appearance of intraneuronal inclusions that are primarily composed of misfolded α-synuclein protein, leading to cytotoxicity and neural death. Recent in vitro and in vivo studies suggest that misfolded α-synuclein may spread transcellularly in a prion-like manner, inducing pathological aggregates in healthy neurons, and is disseminated via secretion of extracellular vesicles. Accordingly, extracellular vesicles derived from brain lysates and cerebrospinal fluid of patients with Parkinson’s disease were shown to facilitate α-synuclein aggregation in healthy cells. Prompted by the hypothesis of Braak et al. that the olfactory bulb is one of the primary propagation sites for the initiation of Parkinson’s disease, we sought to investigate the role of extracellular vesicles in the spread of α-synuclein and progression of Parkinson’s disease through the olfactory bulb. Extracellular vesicles derived from the cerebrospinal fluid of patients diagnosed with Parkinson’s disease or with a nonsynucleinopathy neurodegenerative disorder were administered intranasally to healthy mice, once daily over 4 days. Three months later, mice were subjected to motor and non-motor tests. Functional impairments were elucidated by histochemical analysis of midbrain structures relevant to Parkinson’s disease pathology, 8 months after EVs treatment. Mice treated with extracellular vesicles from the patients with Parkinson’s disease displayed multiple symptoms consistent with prodromal and clinical-phase Parkinson’s disease such as hyposmia, motor behavior impairments, and high anxiety levels. Furthermore, their midbrains showed widespread α-synuclein aggregations, dopaminergic neurodegeneration, neuroinflammation, and altered autophagy activity. Several unconventional pathologies were observed as well, such as α-synuclein aggregations in the red nucleus, growth of premature gray hair, and astrogliosis. Collectively, these data indicate that intranasally administered extracellular vesicles derived from the cerebrospinal fluid of patients with Parkinson’s disease can propagate α-synuclein aggregation in vivo and trigger Parkinson’s disease-like symptoms and pathology in healthy mice.

中文翻译:

来自帕金森病患者的脑脊液来源的细胞外囊泡诱导症状和病理

帕金森病的特征是逐渐出现主要由错误折叠的 α-突触核蛋白组成的神经元内包涵体,从而导致细胞毒性和神经死亡。最近的体外和体内研究表明,错误折叠的 α-突触核蛋白可能以类似朊病毒的方式跨细胞传播,在健康神经元中诱导病理性聚集,并通过细胞外囊泡的分泌进行传播。因此,来自帕金森病患者脑裂解物和脑脊液的细胞外囊泡被证明可以促进健康细胞中的 α-突触核蛋白聚集。由 Braak 等人的假设提示。嗅球是引发帕金森病的主要传播场所之一,我们试图通过嗅球研究细胞外囊泡在 α-突触核蛋白扩散和帕金森病进展中的作用。将来自被诊断患有帕金森病或非突触核蛋白病神经退行性疾病患者脑脊液的细胞外囊泡鼻内给药于健康小鼠,每天一次,持续 4 天。三个月后,对小鼠进行运动和非运动测试。在 EV 治疗后 8 个月,通过对与帕金森病病理学相关的中脑结构进行组织化学分析,阐明了功能障碍。用帕金森病患者的细胞外囊泡治疗的小鼠表现出与前驱和临床阶段帕金森病一致的多种症状,例如嗅觉减退、运动行为障碍、和高焦虑水平。此外,他们的中脑表现出广泛的 α-突触核蛋白聚集、多巴胺能神经变性、神经炎症和自噬活性改变。还观察到几种非常规病理,例如红核中的 α-突触核蛋白聚集、过早白发的生长和星形胶质细胞增生。总的来说,这些数据表明,鼻内给药的源自帕金森病患者脑脊液的细胞外囊泡可以在体内传播 α-突触核蛋白聚集,并在健康小鼠中引发帕金森病样症状和病理。例如红核中的 α-突触核蛋白聚集、过早白发的生长和星形胶质细胞增生。总的来说,这些数据表明,鼻内给药的源自帕金森病患者脑脊液的细胞外囊泡可以在体内传播 α-突触核蛋白聚集,并在健康小鼠中引发帕金森病样症状和病理。例如红核中的 α-突触核蛋白聚集、过早白发的生长和星形胶质细胞增生。总的来说,这些数据表明,鼻内给药的源自帕金森病患者脑脊液的细胞外囊泡可以在体内传播 α-突触核蛋白聚集,并在健康小鼠中引发帕金森病样症状和病理。
更新日期:2022-07-26
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