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Chronic nigral neuromodulation aggravates behavioral deficits and synaptic changes in an α-synuclein based rat model for Parkinson's disease.
Acta Neuropathologica Communications ( IF 6.2 ) Pub Date : 2019-10-22 , DOI: 10.1186/s40478-019-0814-3
Teresa Torre-Muruzabal 1 , Jens Devoght 2 , Chris Van den Haute 1, 3 , Bert Brône 2 , Anke Van der Perren 1 , Veerle Baekelandt 1
Affiliation  

Aggregation of alpha-synuclein (α-SYN) is the pathological hallmark of several diseases named synucleinopathies, including Parkinson's disease (PD), which is the most common neurodegenerative motor disorder. Alpha-SYN has been linked to synaptic function both in physiological and pathological conditions. However, the exact link between neuronal activity, α-SYN toxicity and disease progression in PD is not clear. In this study, we aimed to investigate the effect of chronic neuromodulation in an α-SYN-based rat model for PD using chemogenetics. To do this, we expressed excitatory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) combined with mutant A53T α-SYN, using two different recombinant adeno-associated viral (rAAV) vectors (serotypes 2/7 and 2/8) in rat substantia nigra (SN) and investigated the effect on motor behavior, synapses and neuropathology. We found that chronic neuromodulation aggravates motor deficits induced by α-SYN, without altering dopaminergic neurodegeneration. In addition, neuronal activation led to changes in post-translational modification and subcellular localization of α-SYN, linking neuronal activity to the pathophysiological role of α-SYN in PD.

中文翻译:

慢性黑质神经调节会加剧基于 α-突触核蛋白的帕金森病大鼠模型的行为缺陷和突触变化。

α-突触核蛋白 (α-SYN) 的聚集是多种称为突触核蛋白病的疾病的病理标志,包括帕金森病 (PD),这是最常见的神经退行性运动障碍。Alpha-SYN 与生理和病理条件下的突触功能有关。然而,神经元活动、α-SYN 毒性和 PD 疾病进展之间的确切联系尚不清楚。在这项研究中,我们旨在利用化学遗传学研究慢性神经调节对基于 α-SYN 的 PD 大鼠模型的影响。为此,我们使用两种不同的重组腺相关病毒 (rAAV) 载体(血清型 2/7 和 2/8)在大鼠体内表达了由设计药物独家激活的兴奋性设计受体 (DREADD) 与突变体 A53T α-SYN 组合。 nigra (SN) 并研究了其对运动行为、突触和神经病理学的影响。我们发现,慢性神经调节会加重 α-SYN 引起的运动缺陷,但不会改变多巴胺能神经变性。此外,神经元激活导致 α-SYN 的翻译后修饰和亚细胞定位发生变化,将神经元活动与 α-SYN 在 PD 中的病理生理学作用联系起来。
更新日期:2019-10-22
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