Ledonne Ada, Massaro Cenere Mariangela, Paldino Emanuela, D'Angelo Vincenza, D'Addario Sebastian Luca, Casadei Nicolas, Nobili Annalisa, Berretta Nicola, Fusco Francesca R, Ventura Rossella, Sancesario Giuseppe, Guatteo Ezia, Mercuri Nicola Biagio
Department of Experimental Neuroscience, Santa Lucia Foundation IRCCS, Rome, Italy.
Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
Mov Disord. 2023 Feb;38(2):256-266. doi: 10.1002/mds.29269. Epub 2022 Nov 9.
The accumulation of α-synuclein (α-syn) fibrils in intraneuronal inclusions called Lewy bodies and Lewy neurites is a pathological signature of Parkinson's disease (PD). Although several aspects linked to α-syn-dependent pathology (concerning its spreading, aggregation, and activation of inflammatory and neurodegenerative processes) have been under intense investigation, less attention has been devoted to the real impact of α-syn overexpression on structural and functional properties of substantia nigra pars compacta (SNpc) dopamine (DA) neurons, particularly at tardive stages of α-syn buildup, despite this has obvious relevance to comprehending mechanisms beyond PD progression.
We aimed to determine the consequences of a prolonged α-syn overexpression on somatodendritic morphology and functions of SNpc DA neurons.
We performed immunohistochemistry, stereological DA cell counts, analyses of dendritic arborization, ex vivo patch-clamp recordings, and in vivo DA microdialysis measurements in a 12- to 13-month-old transgenic rat model overexpressing the full-length human α-syn (Snca ) and age-matched wild-type rats.
Aged Snca rats have mild loss of SNpc DA neurons and decreased basal DA levels in the SN. Residual nigral DA neurons display smaller soma and compromised dendritic arborization and, in parallel, increased firing activity, switch in firing mode, and hyperexcitability associated with hypofunction of fast activating/inactivating voltage-gated K channels and Ca - and voltage-activated large conductance K channels. These intrinsic currents underlie the repolarization/afterhyperpolarization phase of action potentials, thus affecting neuronal excitability.
Besides clarifying α-syn-induced pathological landmarks, such evidence reveals compensatory functional mechanisms that nigral DA neurons could adopt during PD progression to counteract neurodegeneration. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
α-突触核蛋白（α-syn）原纤维在称为路易小体和路易神经突的神经元内包涵体中的积累是帕金森病（PD）的病理特征。尽管与α-syn依赖性病理学相关的几个方面（涉及其传播、聚集以及炎症和神经退行性过程的激活）一直受到深入研究，但α-syn过表达对黑质致密部（SNpc）多巴胺（DA）神经元的结构和功能特性的实际影响却较少受到关注，特别是在α-syn积累的晚期阶段，尽管这对于理解PD进展背后的机制具有明显的相关性。
我们旨在确定长期α-syn过表达对SNpc DA神经元的树突形态和功能的影响。
我们在12至13个月大的过表达全长人α-syn（Snca）的转基因大鼠模型和年龄匹配的野生型大鼠中进行了免疫组织化学、立体学DA细胞计数、树突分支分析、离体膜片钳记录和体内DA微透析测量。
老年Snca大鼠的SNpc DA神经元轻度丧失，SN中的基础DA水平降低。残留的黑质DA神经元表现出较小的胞体和受损的树突分支，同时，放电活动增加、放电模式改变以及与快速激活/失活电压门控K通道和Ca²⁺-和电压激活的大电导K通道功能减退相关的过度兴奋。这些内在电流是动作电位复极化/后超极化阶段的基础，从而影响神经元兴奋性。
除了阐明α-syn诱导的病理标志外，这些证据还揭示了黑质DA神经元在PD进展过程中可能采用的补偿性功能机制，以对抗神经退行性变。© 2022作者。《运动障碍》由Wiley Periodicals LLC代表国际帕金森和运动障碍协会出版。
