α-Synuclein-induced dysregulation of neuronal activity contributes to murine dopamine neuron vulnerability.
α-Synuclein-induced dysregulation of neuronal activity contributes to murine dopamine neuron vulnerability.
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DOI：
10.1038/s41531-021-00210-w
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发表时间：
2021-08-18
期刊：
影响因子：
--
通讯作者：
Khoshbouei H
中科院分区：
文献类型：
--
作者：
Dagra A;Miller DR;Lin M;Gopinath A;Shaerzadeh F;Harris S;Sorrentino ZA;Støier JF;Velasco S;Azar J;Alonge AR;Lebowitz JJ;Ulm B;Bu M;Hansen CA;Urs N;Giasson BI;Khoshbouei H
多巴胺神经元的病理生理损伤和功能丧失先于其死亡，并导致帕金森病的早期阶段。中脑腹侧多巴胺能神经元内存在异常的细胞内病理性α-突触核蛋白包涵体是帕金森病的主要特征之一。我们采用分子生物学、电生理学和活细胞成像来研究过度的α-突触核蛋白表达如何改变条件性表达GCaMP 6 f的培养多巴胺神经元中多巴胺能神经元动力学和多巴胺传递的多种特征。我们发现α-突触核蛋白在小鼠（雄性和雌性）多巴胺能神经元中的过表达改变了神经元的放电特性、钙动力学、多巴胺释放、蛋白质表达和形态。此外，长期暴露于D2受体激动剂喹吡罗，挽救了许多由α-突触核蛋白过表达诱导的改变。这些研究表明，神经元活性的α-突触核蛋白失调有助于多巴胺能神经元的脆弱性，并且D2受体活性的调节可以改善病理生理学。这些研究结果提供了机制的见解多巴胺能神经元活性和神经元损失的特点帕金森病的进展与显着的治疗意义的潜在变化。
Pathophysiological damages and loss of function of dopamine neurons precede their demise and contribute to the early phases of Parkinson’s disease. The presence of aberrant intracellular pathological inclusions of the protein α-synuclein within ventral midbrain dopaminergic neurons is one of the cardinal features of Parkinson’s disease. We employed molecular biology, electrophysiology, and live-cell imaging to investigate how excessive α-synuclein expression alters multiple characteristics of dopaminergic neuronal dynamics and dopamine transmission in cultured dopamine neurons conditionally expressing GCaMP6f. We found that overexpression of α-synuclein in mouse (male and female) dopaminergic neurons altered neuronal firing properties, calcium dynamics, dopamine release, protein expression, and morphology. Moreover, prolonged exposure to the D2 receptor agonist, quinpirole, rescues many of the alterations induced by α-synuclein overexpression. These studies demonstrate that α-synuclein dysregulation of neuronal activity contributes to the vulnerability of dopaminergic neurons and that modulation of D2 receptor activity can ameliorate the pathophysiology. These findings provide mechanistic insights into the insidious changes in dopaminergic neuronal activity and neuronal loss that characterize Parkinson’s disease progression with significant therapeutic implications.
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影响因子：
4
作者：
Angelova PR;Ludtmann MH;Horrocks MH;Negoda A;Cremades N;Klenerman D;Dobson CM;Wood NW;Pavlov EV;Gandhi S;Abramov AY
通讯作者：
Abramov AY
影响因子：
5.3
作者：
Benoit-Marand, M;Borrelli, E;Gonon, F
通讯作者：
Gonon, F
影响因子：
5
作者：
CARTER, AJ;MULLER, RE
通讯作者：
MULLER, RE
衣壳血清型和注射的时间决定了新生小鼠脑的AAV转导。
影响因子：
3.7
作者：
Chakrabarty P;Rosario A;Cruz P;Siemienski Z;Ceballos-Diaz C;Crosby K;Jansen K;Borchelt DR;Kim JY;Jankowsky JL;Golde TE;Levites Y
通讯作者：
Levites Y
影响因子：
4.7
作者：
Avelar AJ;Cao J;Newman AH;Beckstead MJ
通讯作者：
Beckstead MJ