Age-dependent effects of A53T alpha-synuclein on behavior and dopaminergic function.
Age-dependent effects of A53T alpha-synuclein on behavior and dopaminergic function.
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DOI：
10.1371/journal.pone.0060378
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Sidhu A
中科院分区：
文献类型：
--
作者：
Oaks AW;Frankfurt M;Finkelstein DI;Sidhu A
在小鼠朊病毒启动子下表达 A53T 突变体人类 α-突触核蛋白是帕金森病最成功的转基因模型之一。 A53T α-突触核蛋白的积累会导致成年小鼠出现严重的运动障碍，导致 8-12 个月大时过早死亡。在较年轻的、出现症状前的动物中，也有报道称运动活动发生改变和类似焦虑的行为。这些先于严重神经病理学发生的行为变化可能源于α-突触核蛋白的非病理性功能，包括单胺神经传递的调节。我们对成人一生中运动活动、焦虑样和抑郁样行为的分析确定了疾病发作前后的扰动。年轻的 A53T 小鼠的膜上多巴胺转运蛋白 (DAT) 的分布增加，这与纹状体再摄取功能的增加有关。 DAT 功能随着年龄的增长而下降，并与神经化学变化相关，包括 β-突触核蛋白和 γ 突触核蛋白表达增加。在多巴胺摄取正常化之前，还观察到纹状体中 Tau 激酶的短暂激活和 Tau 的过度磷酸化。老年 A53T 小鼠黑质致密部神经元数量减少，但纹状体中等多刺神经元树突棘密度基本保持不变。这些发现强调了突触核蛋白家族蛋白和 Tau 磷酸化在对黑质纹状体通路多巴胺能功能障碍的反应中的参与。
Expression of A53T mutant human alpha-synuclein under the mouse prion promoter is among the most successful transgenic models of Parkinson's disease. Accumulation of A53T alpha-synuclein causes adult mice to develop severe motor impairment resulting in early death at 8–12 months of age. In younger, pre-symptomatic animals, altered motor activity and anxiety-like behaviors have also been reported. These behavioral changes, which precede severe neuropathology, may stem from non-pathological functions of alpha-synuclein, including modulation of monoamine neurotransmission. Our analysis over the adult life-span of motor activity, anxiety-like, and depressive-like behaviors identifies perturbations both before and after the onset of disease. Young A53T mice had increased distribution of the dopamine transporter (DAT) to the membrane that was associated with increased striatal re-uptake function. DAT function decreased with aging, and was associated with neurochemical alterations that included increased expression of beta-synuclein and gamma synuclein. Prior to normalization of dopamine uptake, transient activation of Tau kinases and hyperphosphorylation of Tau in the striatum were also observed. Aged A53T mice had reduced neuron counts in the substantia nigra pars compacta, yet striatal medium spiny neuron dendritic spine density was largely maintained. These findings highlight the involvement of the synuclein family of proteins and phosphorylation of Tau in the response to dopaminergic dysfunction of the nigrostriatal pathway.
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影响因子：
16.2
作者：
Giasson, BI;Duda, JE;Lee, VMY
通讯作者：
Lee, VMY
影响因子：
5.3
作者：
Frasier, M;Walzer, M;Wolozin, B
通讯作者：
Wolozin, B
缺氧成像剂CUII（ATSM）具有神经保护作用，并改善了帕金森氏病多种动物模型的运动和认知功能。
DOI：
10.1084/jem.20112285
发表时间：
2012-04-09
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hung LW;Villemagne VL;Cheng L;Sherratt NA;Ayton S;White AR;Crouch PJ;Lim S;Leong SL;Wilkins S;George J;Roberts BR;Pham CL;Liu X;Chiu FC;Shackleford DM;Powell AK;Masters CL;Bush AI;O'Keefe G;Culvenor JG;Cappai R;Cherny RA;Donnelly PS;Hill AF;Finkelstein DI;Barnham KJ
通讯作者：
Barnham KJ
影响因子：
4.8
作者：
Emmer, Kristel L.;Waxman, Elisa A.;Giasson, Benoit I.
通讯作者：
Giasson, Benoit I.
影响因子：
2.3
作者：
Frankfurt, Maya;Salas-Ramirez, Kaliris;Friedman, Eitan;Luine, Victoria
通讯作者：
Luine, Victoria