Andreska Thomas, Lüningschrör Patrick, Wolf Daniel, McFleder Rhonda L, Ayon-Olivas Maurilyn, Rattka Marta, Drechsler Christine, Perschin Veronika, Blum Robert, Aufmkolk Sarah, Granado Noelia, Moratalla Rosario, Sauer Markus, Monoranu Camelia, Volkmann Jens, Ip Chi Wang, Stigloher Christian, Sendtner Michael
Institute of Clinical Neurobiology, University Hospital Wuerzburg, 97078 Wuerzburg, Germany.
Department of Neurology, University Hospital Wuerzburg, 97080 Wuerzburg, Germany.
Cell Rep. 2023 Jun 27;42(6):112575. doi: 10.1016/j.celrep.2023.112575. Epub 2023 May 29.
Disturbed motor control is a hallmark of Parkinson's disease (PD). Cortico-striatal synapses play a central role in motor learning and adaption, and brain-derived neurotrophic factor (BDNF) from cortico-striatal afferents modulates their plasticity via TrkB in striatal medium spiny projection neurons (SPNs). We studied the role of dopamine in modulating the sensitivity of direct pathway SPNs (dSPNs) to BDNF in cultures of fluorescence-activated cell sorting (FACS)-enriched D1-expressing SPNs and 6-hydroxydopamine (6-OHDA)-treated rats. DRD1 activation causes enhanced TrkB translocation to the cell surface and increased sensitivity for BDNF. In contrast, dopamine depletion in cultured dSPN neurons, 6-OHDA-treated rats, and postmortem brain of patients with PD reduces BDNF responsiveness and causes formation of intracellular TrkB clusters. These clusters associate with sortilin related VPS10 domain containing receptor 2 (SORCS-2) in multivesicular-like structures, which apparently protects them from lysosomal degradation. Thus, impaired TrkB processing might contribute to disturbed motor function in PD.
运动控制障碍是帕金森病（PD）的一个标志。皮质-纹状体突触在运动学习和适应中起核心作用，来自皮质-纹状体传入神经的脑源性神经营养因子（BDNF）通过纹状体中等棘状投射神经元（SPN）中的TrkB调节其可塑性。我们在荧光激活细胞分选（FACS）富集的表达D1的SPN培养物和6-羟基多巴胺（6-OHDA）处理的大鼠中研究了多巴胺在调节直接通路SPN（dSPN）对BDNF敏感性中的作用。DRD1激活导致TrkB向细胞表面的转位增强，并增加对BDNF的敏感性。相反，培养的dSPN神经元、6-OHDA处理的大鼠以及PD患者的死后大脑中的多巴胺耗竭会降低BDNF反应性，并导致细胞内TrkB簇的形成。这些簇在多囊泡样结构中与含sortilin相关VPS10结构域受体2（SORCS-2）相关联，这显然保护它们免受溶酶体降解。因此，TrkB加工受损可能导致PD中的运动功能障碍。
