Unveiling the role of p62 at modulating astrocyte reactivity and its implications for ALS/FTD

揭示 p62 在调节星形胶质细胞反应性方面的作用及其对 ALS/FTD 的影响

• 批准号: 2748674
• 金额: --
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2748674
• 关键词: Unveiling; role; p62; modulating; astrocyte

Amyotrophic lateral sclerosis (ALS) is a fatal late-onset neurodegenerative disease that targets the function and survival of motor neurons in the spinal cord and cortex (1). Notably, ALS shares numerous genetic, clinical, and pathological features with frontotemporal dementia (FTD), leading to their recognition as part of a disease spectrum termed ALS/FTD. Currently, no disease-modifying treatments are available for these devastating illnesses (1). The accumulation of protein aggregates is a major hallmark of ALS and FTD, suggesting the compromise of protein clearance pathways in the pathogenesis of these diseases (2). One of the ALS/FTD-linked genes encodes sequestosome 1 (SQSTM1/p62), a multi-domain scaffold protein involved in targeting cargo for degradation via autophagy and the ubiquitin-proteasome system. Additionally, p62 serves as a signalling hub for various cellular signal transduction cascades, thereby regulating multiple cellular functions, including the activation of mTORC1 in nutrient sensing, the regulation of inflammation and apoptosis through activation of the nuclear factor kappa-B and the antioxidant response via activation of Keap1-NF-E2-related factor 2 (Nrf2) pathway (3). Although less extensively investigated, the presence of p62-positive inclusions is not limited to neurons but also extends to astrocytes in the temporal cortex of patients with ALS/FTD (4,5,6,7), as well as astrocytes from FTD cases (8,9) and glial cells in human tauopathies and synucleopathies (10). Despite some evidence, a detailed characterization of the pathology associated with astrocytic p62 in ALS/FTD is currently missing. In neurodegenerative diseases like ALS and FTD, astrocytes become reactive as part of a conserved physiological response that ultimately result in the gain of new functions and loss or upregulation of homeostatic ones (11). In ALS and FTD, reactive astrocytes contribute to neuron toxicity through non-cell autonomous effects (12). When we modelled astrocyte reactivity in primary mouse astrocytes treated with cytokines that simulate the disease brain environment, we observed a significant increase in the levels of p62 likely due to the transcriptional upregulation of its gene, suggesting that p62 may play a significant role in modulating astrocyte reactivity. While multiple lines of evidence implicate p62 and autophagic degradation in ALS and FTD pathology, less is known about the functional implications for p62 on astrocyte reactivity and its non-cell autonomous consequences in disease. Understanding the role of p62 in astrocyte reactivity is crucial for the development of future therapeutic strategies aimed at restoring normal astrocyte function and consequently improving neuronal function and protection from injury and disease.

肌萎缩侧索硬化症（ALS）是一种致命的迟发性神经退行性疾病，其靶向脊髓和皮质中运动神经元的功能和存活（1）。值得注意的是，ALS与额颞叶痴呆（FTD）具有许多遗传、临床和病理特征，导致其被识别为称为ALS/FTD的疾病谱的一部分。目前，对于这些毁灭性的疾病，没有疾病修饰疗法可用（1）。 蛋白质聚集体的蓄积是ALS和FTD的主要标志，表明蛋白质清除途径在这些疾病的发病机制中受到损害（2）。ALS/FTD连锁基因之一编码螯合体1（SQSTM 1/p62），其是一种多结构域支架蛋白，参与靶向货物以通过自噬和泛素-蛋白酶体系统降解。此外，p62作为各种细胞信号转导级联的信号中枢，从而调节多种细胞功能，包括在营养感测中激活mTORC 1，通过激活核因子κ B调节炎症和凋亡，以及通过激活Keap 1-NF-E2相关因子2（Nrf 2）途径调节抗氧化反应（3）。 虽然研究较少，但p62阳性包涵体的存在不仅限于神经元，还扩展到ALS/FTD患者颞叶皮质中的星形胶质细胞（4、5、6、7），以及FTD病例中的星形胶质细胞（8、9）和人tau蛋白病和突触核蛋白病中的神经胶质细胞（10）。尽管有一些证据，但目前尚缺乏ALS/FTD中星形胶质细胞p62相关病理学的详细描述。 在ALS和FTD等神经退行性疾病中，星形胶质细胞作为保守生理反应的一部分变得具有反应性，最终导致获得新功能和丧失或上调稳态功能（11）。在ALS和FTD中，反应性星形胶质细胞通过非细胞自主效应导致神经元毒性（12）。当我们在用模拟疾病脑环境的细胞因子处理的原代小鼠星形胶质细胞中模拟星形胶质细胞反应性时，我们观察到p62水平的显著增加，这可能是由于其基因的转录上调，表明p62可能在调节星形胶质细胞反应性中起重要作用。虽然多条证据表明p62和自噬降解在ALS和FTD病理学中存在，但关于p62对星形胶质细胞反应性的功能影响及其在疾病中的非细胞自主后果知之甚少。 了解p62在星形胶质细胞反应性中的作用对于未来旨在恢复正常星形胶质细胞功能并因此改善神经元功能和保护免受损伤和疾病的治疗策略的发展至关重要。