Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, United States.
Department of Neurobiology, Northwestern University, Chicago, United States.
Elife. 2020 Oct 2;9:e58997. doi: 10.7554/eLife.58997.
LRRK2 is a kinase expressed in striatal spiny projection neurons (SPNs), cells which lose dopaminergic input in Parkinson's disease (PD). R1441C and G2019S are the most common pathogenic mutations of LRRK2. How these mutations alter the structure and function of individual synapses on direct and indirect pathway SPNs is unknown and may reveal pre-clinical changes in dopamine-recipient neurons that predispose toward disease. Here, R1441C and G2019S knock-in mice enabled thorough evaluation of dendritic spines and synapses on pathway-identified SPNs. Biochemical synaptic preparations and super-resolution imaging revealed increased levels and altered organization of glutamatergic AMPA receptors in LRRK2 mutants. Relatedly, decreased frequency of miniature excitatory post-synaptic currents accompanied changes in dendritic spine nano-architecture, and single-synapse currents, evaluated using two-photon glutamate uncaging. Overall, LRRK2 mutations reshaped synaptic structure and function, an effect exaggerated in R1441C dSPNs. These data open the possibility of new neuroprotective therapies aimed at SPN synapse function, prior to disease onset.
LRRK2 是一种在纹状体棘突投射神经元（SPN）中表达的激酶，这些神经元在帕金森病（PD）中失去多巴胺能输入。R1441C 和 G2019S 是 LRRK2 最常见的致病性突变。这些突变如何改变直接和间接通路 SPN 上单个突触的结构和功能尚不清楚，可能揭示了使多巴胺受体神经元易患疾病的临床前变化。在这里，R1441C 和 G2019S 敲入小鼠使我们能够彻底评估通路鉴定的 SPN 上的树突棘和突触。生化突触制剂和超分辨率成像显示 LRRK2 突变体中谷氨酸能 AMPA 受体的水平增加和组织改变。相关地，随着树突棘纳米结构和使用双光子谷氨酸非光解的单突触电流的变化，减小了微小兴奋性突触后电流的频率。总体而言，LRRK2 突变重塑了突触的结构和功能，在 R1441C dSPN 中这种效应更为明显。这些数据为针对 SPN 突触功能的新神经保护疗法开辟了可能性，从而可以在疾病发作之前进行治疗。
