Santos Altair Brito Dos, Thaneshwaran Siganya, Ali Lara Kamal, Leguizamón César Ramón Romero, Wang Yang, Kristensen Morten Pilgaard, Langkilde Annette E, Kohlmeier Kristi A
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2100, Denmark.
Dept of Neuroscience, University of Copenhagen, Copenhagen, 2200, Denmark.
Cell Biosci. 2023 Sep 14;13(1):172. doi: 10.1186/s13578-023-01105-4.
Sleep disorders (SDs) are a symptom of the prodromal phase of neurodegenerative disorders that are mechanistically linked to the protein α-synuclein (α-syn) including Parkinson's disease (PD). SDs during the prodromal phase could result from neurodegeneration induced in state-controlling neurons by accumulation of α-syn predominant early in the disease, and consistent with this, we reported the monomeric form of α-syn (monomeric α-syn; α-syn) caused cell death in the laterodorsal tegmental nucleus (LDT), which controls arousal as well as the sleep and wakefulness state. However, we only examined the male LDT, and since sex is considered a risk factor for the development of α-syn-related diseases including prodromal SDs, the possibility exists of sex-based differences in α-syn effects. Accordingly, we examined the hypothesis that α-syn exerts differential effects on membrane excitability, intracellular calcium, and cell viability in the LDT of females compared to males.
Patch clamp electrophysiology, bulk load calcium imaging, and cell death histochemistry were used in LDT brain slices to monitor responses to α-syn and effects of GABA receptor acting agents.
Consistent with our hypothesis, we found differing effects of α-syn on female LDT neurons when compared to male. In females, α-syn induced a decrease in membrane excitability and heightened reductions in intracellular calcium, which were reliant on functional inhibitory acid transmission, as well as decreased the amplitude and frequency of spontaneous excitatory postsynaptic currents (sEPSCs) with a concurrent reduction in action potential firing rate. Cell viability studies showed higher α-syn-mediated neurodegeneration in males compared to females that depended on inhibitory amino acid transmission. Further, presence of GABA receptor agonists was associated with reduced cell death in males.
When taken together, we conclude that α-syn induces a sex-dependent effect on LDT neurons involving a GABA receptor-mediated mechanism that is neuroprotective. Understanding the potential sex differences in neurodegenerative processes, especially those occurring early in the disease, could enable implementation of sex-based strategies to identify prodromal PD cases, and promote efforts to illuminate new directions for tailored treatment and management of PD.
睡眠障碍（SDs）是神经退行性疾病前驱期的一种症状，其在机制上与包括帕金森病（PD）在内的蛋白质α-突触核蛋白（α-syn）相关联。前驱期的睡眠障碍可能是由于疾病早期α-syn的积累导致状态控制神经元发生神经退行性变所致，与此一致的是，我们报道了α-突触核蛋白的单体形式（单体α-syn；α-syn）在控制觉醒以及睡眠和清醒状态的脑桥背外侧被盖核（LDT）中导致细胞死亡。然而，我们仅研究了雄性LDT，并且由于性别被认为是包括前驱期睡眠障碍在内的α-syn相关疾病发生发展的一个风险因素，因此α-syn的作用可能存在基于性别的差异。因此，我们检验了这样一个假设，即与雄性相比，α-syn对雌性LDT中的膜兴奋性、细胞内钙和细胞活力具有不同的影响。
在LDT脑片中使用膜片钳电生理学、批量加载钙成像和细胞死亡组织化学来监测对α-syn的反应以及GABA受体作用剂的影响。
与我们的假设一致，我们发现与雄性相比，α-syn对雌性LDT神经元有不同的影响。在雌性中，α-syn导致膜兴奋性降低以及细胞内钙的减少加剧，这依赖于功能性抑制性氨基酸传递，同时还降低了自发兴奋性突触后电流（sEPSCs）的幅度和频率，并伴有动作电位发放率的降低。细胞活力研究表明，与雌性相比，雄性中α-syn介导的神经退行性变更高，这依赖于抑制性氨基酸传递。此外，GABA受体激动剂的存在与雄性细胞死亡减少有关。
综合来看，我们得出结论，α-syn对LDT神经元产生性别依赖性影响，涉及一种GABA受体介导的神经保护机制。了解神经退行性过程中潜在的性别差异，尤其是疾病早期发生的差异，可能有助于实施基于性别的策略来识别前驱期PD病例，并推动为PD的定制治疗和管理探索新方向。
