Paldino Emanuela, Migliorato Giorgia, Fusco Francesca R
Laboratory of Neuroanatomy, Fondazione Santa Lucia IRCCS, Rome, Italy.
Department of Life Sciences, University of Trieste, Trieste, Italy.
Front Cell Neurosci. 2024 Feb 20;18:1360066. doi: 10.3389/fncel.2024.1360066. eCollection 2024.
Mechanisms of tissue damage in Huntington's disease (HD) involve excitotoxicity, mitochondrial damage, and neuroinflammation, including microglia activation. CD47 is a membrane protein that interacts with the inhibitory immunoreceptor SIRPα. Engagement of SIRPα by CD47 provides a downregulatory signal that inhibits host cell phagocytosis, promoting a "don't-eat-me" signal. These proteins are involved in the immune response and are downmodulated in inflammatory diseases. The involvement of inflammation and of the inflammasome in HD has already been described. In this study, we focused on other factors that can be involved in the unregulated inflammatory response that accelerates and exacerbate the neurodegenerative process in HD. Our results show that CD47 on striatal neurons decreased in HD mice, while it increased in wild type mice with age. SIRPα, on the other hand, was present in neurons in the wild type and increases in the R6/2 mice at all stages. Recruitment of SIRPα and binding to CD47 promotes the activation through phosphorylating events of non-receptor protein tyrosine phosphatase SHP-1 and SHP-2 in neurons and microglia. SHP phosphatases are able to curb the activity of NLRP3 inflammasome thereby reducing the detrimental effect of neuroinflammation. Such activity is mediated by the inhibition (dephosphorylation) of the proteins signal transducer and activator of transcription (STAT). We found that activated SHP-1 was present in microglia and neurons of WT mice at 5 and 13 weeks, increasing with time; while in R6/2 it was not localized in neurons but only in microglia, where it decreases with time. Consequently, STAT1 was overexpressed in neurons of R6/2 mice, as an effect of lack of modulation by SHP-1. Thus, our results shed light on the pathophysiology of neuronal damage, on one hand, paving the way toward a modulation of signal transducer proteins by specific inhibitors to achieve neuroprotection in HD, on the other.
亨廷顿舞蹈病（HD）中的组织损伤机制涉及兴奋性毒性、线粒体损伤和神经炎症，包括小胶质细胞激活。CD47是一种与抑制性免疫受体信号调节蛋白α（SIRPα）相互作用的膜蛋白。CD47与SIRPα的结合提供了一个下调信号，抑制宿主细胞吞噬作用，从而产生一个“别吃我”信号。这些蛋白质参与免疫反应，在炎症性疾病中表达下调。炎症和炎性小体在HD中的作用已有相关描述。在本研究中，我们关注了其他可能参与加速和加剧HD神经退行性过程的失控炎症反应的因素。我们的结果表明，HD小鼠纹状体神经元上的CD47减少，而野生型小鼠的CD47随年龄增加。另一方面，野生型神经元中存在SIRPα，R6/2小鼠在所有阶段SIRPα均增加。SIRPα的募集及其与CD47的结合通过神经元和小胶质细胞中非受体蛋白酪氨酸磷酸酶SHP-1和SHP-2的磷酸化事件促进激活。SHP磷酸酶能够抑制NLRP3炎性小体的活性，从而降低神经炎症的有害影响。这种活性是通过抑制信号转导和转录激活因子（STAT）蛋白的磷酸化（去磷酸化）介导的。我们发现，野生型小鼠在5周和13周时，活化的SHP-1存在于小胶质细胞和神经元中，并随时间增加；而在R6/2小鼠中，它不在神经元中定位，仅存在于小胶质细胞中，且随时间减少。因此，由于缺乏SHP-1的调节，STAT1在R6/2小鼠的神经元中过度表达。因此，我们的结果一方面揭示了神经元损伤的病理生理学，另一方面为通过特定抑制剂调节信号转导蛋白以实现HD的神经保护铺平了道路。
