Early α-synuclein/synapsin III co-accumulation, nigrostriatal dopaminergic synaptopathy and denervation in the MPTPp mouse model of Parkinson's Disease.

IF 4.6 2区 医学 Q1 NEUROSCIENCES Experimental Neurology Pub Date : 2024-11-03 DOI:10.1016/j.expneurol.2024.115040
Marcello Serra, Gaia Faustini, Viviana Brembati, Maria Antonietta Casu, Marina Pizzi, Micaela Morelli, Annalisa Pinna, Arianna Bellucci
{"title":"Early α-synuclein/synapsin III co-accumulation, nigrostriatal dopaminergic synaptopathy and denervation in the MPTPp mouse model of Parkinson's Disease.","authors":"Marcello Serra, Gaia Faustini, Viviana Brembati, Maria Antonietta Casu, Marina Pizzi, Micaela Morelli, Annalisa Pinna, Arianna Bellucci","doi":"10.1016/j.expneurol.2024.115040","DOIUrl":null,"url":null,"abstract":"<p><p>Parkinson's disease (PD) is characterized by the loss of nigrostriatal dopaminergic neurons and the presence of Lewy bodies (LB), intraneuronal inclusions mainly composed of α-synuclein (α-Syn) fibrils. Compelling evidence supports that, in PD brains, synapses are the sites where neurodegeneration initiates several years before the manifestation of motor symptoms. Furthermore, the amount of α-Syn deposited at synaptic terminals is several orders greater than that constituting LB. This hints that pathological synaptic α-Syn aggregates may be the main trigger for the retrograde synapse-to-cell body degeneration pattern characterizing early prodromal phases of PD. Identifying reliable biomarkers of synaptopathy is therefore crucial for early diagnosis. Here, we studied the alterations of key dopaminergic and non-dopaminergic striatal synaptic markers during the initial phases of axonal and cell body degeneration in mice subjected to 3 or 10 administrations of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine + probenecid (MPTPp), a model for early prodromal PD. We found that MPTPp administration resulted in progressive deposition of α-Syn, advancing from synaptic terminals to axons and dopaminergic neuron cell bodies. This was accompanied by marked co-accumulation of Synapsin III (Syn III), a synaptic protein previously identified as a component of α-Syn fibrils in post-mortem PD brains and as a main stabilizer of α-Syn aggregates, as well as very early and severe reduction of vesicular monoamine transporter 2 (VMAT2), dopamine transporter (DAT) and tyrosine hydroxylase (TH) immunoreactivity in nigrostriatal neurons. Results also showed that striatal α-Syn accumulation and VMAT2 decrease, unlike other markers, did not recover following washout from 10 MPTPp administrations, supporting that these changes were precocious and severe. Finally, we found that early changes in striatal α-Syn, Syn III, VMAT2 and DAT observed following 3 MPTPp administrations, correlated with nigrostriatal neuron loss after 10 MPTPp administrations. These findings indicate that α-Syn/Syn III co-deposition characterizes very early stages of striatal dopaminergic dysfunction in the MPTPp model and highlight that VMAT2 and Syn III could be two reliable molecular imaging biomarkers to predict dopamine neuron denervation and estimate α-Syn-related synaptopathy in prodromal and early symptomatic phases of PD.</p>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":4.6000,"publicationDate":"2024-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Experimental Neurology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.expneurol.2024.115040","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0

Abstract

Parkinson's disease (PD) is characterized by the loss of nigrostriatal dopaminergic neurons and the presence of Lewy bodies (LB), intraneuronal inclusions mainly composed of α-synuclein (α-Syn) fibrils. Compelling evidence supports that, in PD brains, synapses are the sites where neurodegeneration initiates several years before the manifestation of motor symptoms. Furthermore, the amount of α-Syn deposited at synaptic terminals is several orders greater than that constituting LB. This hints that pathological synaptic α-Syn aggregates may be the main trigger for the retrograde synapse-to-cell body degeneration pattern characterizing early prodromal phases of PD. Identifying reliable biomarkers of synaptopathy is therefore crucial for early diagnosis. Here, we studied the alterations of key dopaminergic and non-dopaminergic striatal synaptic markers during the initial phases of axonal and cell body degeneration in mice subjected to 3 or 10 administrations of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine + probenecid (MPTPp), a model for early prodromal PD. We found that MPTPp administration resulted in progressive deposition of α-Syn, advancing from synaptic terminals to axons and dopaminergic neuron cell bodies. This was accompanied by marked co-accumulation of Synapsin III (Syn III), a synaptic protein previously identified as a component of α-Syn fibrils in post-mortem PD brains and as a main stabilizer of α-Syn aggregates, as well as very early and severe reduction of vesicular monoamine transporter 2 (VMAT2), dopamine transporter (DAT) and tyrosine hydroxylase (TH) immunoreactivity in nigrostriatal neurons. Results also showed that striatal α-Syn accumulation and VMAT2 decrease, unlike other markers, did not recover following washout from 10 MPTPp administrations, supporting that these changes were precocious and severe. Finally, we found that early changes in striatal α-Syn, Syn III, VMAT2 and DAT observed following 3 MPTPp administrations, correlated with nigrostriatal neuron loss after 10 MPTPp administrations. These findings indicate that α-Syn/Syn III co-deposition characterizes very early stages of striatal dopaminergic dysfunction in the MPTPp model and highlight that VMAT2 and Syn III could be two reliable molecular imaging biomarkers to predict dopamine neuron denervation and estimate α-Syn-related synaptopathy in prodromal and early symptomatic phases of PD.

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
帕金森病 MPTPp 小鼠模型的早期α-突触核蛋白/突触核蛋白 III 共同积累、黑质纹状体多巴胺能突触病变和神经支配。
帕金森病(PD)的特征是黑质多巴胺能神经元的丧失和路易体(LB)的存在,路易体是一种主要由α-突触核蛋白(α-Syn)纤维组成的内含物。有令人信服的证据表明,在帕金森病患者的大脑中,突触是神经变性的起始部位,比运动症状出现早数年。此外,沉积在突触末端的α-Syn的数量比构成LB的α-Syn多几个数量级。这表明,病理突触α-Syn聚集可能是导致逆行性突触-细胞体变性模式的主要诱因,而这种模式正是帕金森病早期前驱阶段的特征。因此,确定突触病的可靠生物标志物对于早期诊断至关重要。在这里,我们研究了小鼠在轴突和细胞体变性的初期阶段多巴胺能和非多巴胺能纹状体突触关键标记物的变化,这些标记物是在给小鼠注射3次或10次1-甲基-4-苯基-1,2,3,6-四氢吡啶+丙磺舒(MPTPp)后出现的。我们发现,服用 MPTPp 会导致 α-Syn 逐渐沉积,并从突触末端向轴突和多巴胺能神经元细胞体推进。与此同时,黑质神经元中的囊泡单胺转运体 2(VMAT2)、多巴胺转运体(DAT)和酪氨酸羟化酶(TH)的免疫活性也在极早期出现严重下降。结果还显示,与其他标记物不同,纹状体α-Syn的积累和VMAT2的减少在10次MPTPp给药冲洗后并没有恢复,这证明这些变化是早熟和严重的。最后,我们发现在注射 3 次 MPTPp 后观察到的纹状体 α-Syn、Syn III、VMAT2 和 DAT 的早期变化与注射 10 次 MPTPp 后黑质神经元的缺失相关。这些研究结果表明,在 MPTPp 模型中,α-Syn/Syn III 协同沉积是纹状体多巴胺能功能障碍的早期阶段的特征,并强调 VMAT2 和 Syn III 可作为两种可靠的分子成像生物标记物,用于预测多巴胺神经元去神经化,并估计与α-Syn 相关的突触病变在帕金森病前驱期和早期症状期的情况。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
Experimental Neurology
Experimental Neurology 医学-神经科学
CiteScore
10.10
自引率
3.80%
发文量
258
审稿时长
42 days
期刊介绍: Experimental Neurology, a Journal of Neuroscience Research, publishes original research in neuroscience with a particular emphasis on novel findings in neural development, regeneration, plasticity and transplantation. The journal has focused on research concerning basic mechanisms underlying neurological disorders.
期刊最新文献
Anesthesia/surgery leads to blood-brain barrier disruption via the transcellular and paracellular pathways, and postoperative delirium-like behavior: A comparative study in mice of different ages. Temporal development of seizure threshold and spontaneous seizures after neonatal asphyxia and the effect of prophylactic treatment with midazolam in rats. Early α-synuclein/synapsin III co-accumulation, nigrostriatal dopaminergic synaptopathy and denervation in the MPTPp mouse model of Parkinson's Disease. Comparing white and gray matter responses to lobar intracerebral hemorrhage in piglets and the effects of deferoxamine. Multifaceted role of thrombin in subarachnoid hemorrhage: Focusing on cerebrospinal fluid circulation disorder.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1