Parkinson's-linked LRRK2-G2019S derails AMPAR trafficking, mobility and composition in striatum with cell-type and subunit specificity.
Parkinson's-linked LRRK2-G2019S derails AMPAR trafficking, mobility and composition in striatum with cell-type and subunit specificity.
复制标题
帕金森病相关的 LRRK2-G2019S 会破坏纹状体中 AMPAR 的运输、移动性和组成，并具有细胞类型和亚基特异性。
DOI：
10.1101/2023.10.13.562231
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Benson,DeannaL
中科院分区：
文献类型：
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作者：
Gupta,Swati;Guevara,ChristopherA;Tielemans,Alexander;Huntley,GeorgeW;Benson,DeannaL
帕金森病 (PD) 是一种影响多个大脑系统和回路的多因素疾病。虽然由脑干多巴胺神经元退化引起的运动症状定义，但基于额纹状体的认知功能的衰弱性非运动异常很常见，出现得很早，并且最初与多巴胺无关。 Lrrk2 中表达 PD 相关 G2019S 错义突变的年轻成年小鼠在基于额纹状体的认知任务中也表现出缺陷。在小鼠和人类中，认知功能需要通过细胞表面α-氨基-3-羟基-5-甲基-4-异恶唑丙酸型谷氨酸受体（AMPAR）的运输来动态调整谷氨酸突触强度，但尚不清楚LRRK2突变如何影响纹状体投射神经元（SPN）中AMPAR运输的动态特征。在这里，我们使用 Lrrk2G2019Sknockin 小鼠来证明，背内侧纹状体中突变 SPN 的表面 AMPAR 亚基化学计量发生了生化和功能上的改变，有利于 GluA1 而非 GluA2 的掺入。含有 GluA1 的 AMPAR 能够抵抗细胞表面的内化，导致 GluA1 在突触内外的表面上过度积累。这对通常支持突触强化的运输动态产生了负面影响，因为含 GluA1 的 AMPAR 未能响应增强刺激而在突触处增加，并且表面流动性显着降低。表面含有 GluA2 的 AMPAR 在突触中以正常水平表达，表明亚基选择性损伤。 GluA1 的异常表面积累与 PKA 活性无关，并且仅限于 D1R SPN。由于 LRRK2 突变被认为是常见的 PD 致病途径的一部分，因此我们的数据表明 AMPAR 组成和运输的持续、纹状体细胞类型特异性变化会导致与 PD 相关的认知或其他损伤。
Parkinson’s disease (PD) is a multifactorial disease that affects multiple brain systems and circuits. While defined by motor symptoms caused by degeneration of brainstem dopamine neurons, debilitating non-motor abnormalities in fronto-striatal-based cognitive function are common, appear early, and are initially independent of dopamine. Young adult mice expressing the PD-associated G2019S missense mutation inLrrk2also exhibit deficits in fronto-striatal-based cognitive tasks. In mice and humans, cognitive functions require dynamic adjustments in glutamatergic synapse strength through cell-surface trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptors (AMPARs), but it is unknown how LRRK2 mutation impacts dynamic features of AMPAR trafficking in striatal projection neurons (SPNs). Here, we usedLrrk2G2019Sknockin mice to show that surface AMPAR subunit stoichiometry is altered biochemically and functionally in mutant SPNs in dorsomedial striatum to favor the incorporation of GluA1 over GluA2. GluA1-containing AMPARs were resistant to internalization from the cell surface, leaving an excessive accumulation of GluA1 on the surface within and outside synapses. This negatively impacted trafficking dynamics that normally support synapse strengthening, as GluA1-containing AMPARs failed to increase at synapses in response to a potentiating stimulus and showed significantly reduced surface mobility. Surface GluA2-containing AMPARs were expressed at normal levels in synapses, indicating subunit-selective impairment. Abnormal surface accumulation of GluA1 was independent of PKA activity and was limited to D1R SPNs. Since LRRK2 mutation is thought to be part of a common PD pathogenic pathway, our data suggest that sustained, striatal cell-type specific changes in AMPAR composition and trafficking contribute to cognitive or other impairments associated with PD.