GFAP hyperpalmitoylation exacerbates astrogliosis and neurodegenerative pathology in PPT1-deficient mice.
GFAP hyperpalmitoylation exacerbates astrogliosis and neurodegenerative pathology in PPT1-deficient mice.
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GFAP 过度棕榈酰化加剧 PPT1 缺陷小鼠的星形胶质细胞增生和神经退行性病理
DOI：
10.1073/pnas.2022261118
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发表时间：
2021-03-30
影响因子：
11.1
通讯作者：
Kong E
中科院分区：
文献类型：
--
作者：
Yuan W;Lu L;Rao M;Huang Y;Liu CE;Liu S;Zhao Y;Liu H;Zhu J;Chao T;Wu C;Ren J;Lv L;Li W;Qi S;Liang Y;Yue S;Gao J;Zhang Z;Kong E
本研究报告称，中间丝蛋白胶质纤维酸性蛋白（GFAP）会发生蛋白质棕榈酰化修饰。GFAP表达及棕榈酰化水平的升高与星形胶质细胞增殖和星形胶质细胞增生症有关。我们证实，GFAP的棕榈酰化受PPT1调控，PPT1是一种棕榈酰蛋白硫酯酶，与一种儿童神经退行性疾病——婴儿型神经元蜡样质脂褐质沉积症相关。在PPT1功能缺失的小鼠中，GFAP的棕榈酰化缺陷突变体可减轻星形胶质细胞增生症及并发的病理症状。我们得出结论，棕榈酰化GFAP的积累有助于星形胶质细胞增生症和神经退行性变的发病机制，这表明靶向GFAP中发生修饰的半胱氨酸，可能是治疗婴儿型神经元蜡样质脂褐质沉积症及其他神经退行性疾病的一种潜在治疗策略。
蛋白质棕榈酰化与去棕榈酰化的动态平衡对于各种组织，尤其是中枢神经系统（CNS）的正常生理功能至关重要。催化去棕榈酰化过程的PPT1功能障碍（PPT1基因敲入小鼠，即婴儿型神经元蜡样质脂褐质沉积症[INCL]小鼠模型），会导致严重的神经退行性变，并伴有大脑中严重的星形胶质细胞增生症。通过棕榈酰化蛋白质组学，我们试图确定可能导致中枢神经系统发病机制的关键因素，结果发现了胶质纤维酸性蛋白（GFAP），这表明GFAP可能发生棕榈酰化。关于GFAP在体内是否确实发生棕榈酰化，以及GFAP的棕榈酰化如何参与神经病理过程等问题，仍有待探索和研究。在此，我们表明GFAP在体外和体内都易于发生棕榈酰化；具体而言，半胱氨酸 - 291是GFAP中唯一发生棕榈酰化的残基。有趣的是，研究发现棕榈酰化的GFAP在体外可促进星形胶质细胞增殖。此外，我们还表明PPT1可使GFAP去棕榈酰化，且在PPT1基因敲入小鼠中，棕榈酰化GFAP的水平大幅上调，这使我们推测，棕榈酰化GFAP水平的升高可能在体内加速星形胶质细胞增殖，并最终导致INCL中的星形胶质细胞增生症。事实上，通过将GFAP中的半胱氨酸 - 291突变为丙氨酸来阻断棕榈酰化，可减轻星形胶质细胞增生症，值得注意的是，还能减轻PPT1基因敲入小鼠中并发的神经退行性病理症状。综上所述，这些研究结果表明，过度棕榈酰化的GFAP在调节中枢神经系统中星形胶质细胞增生症和神经退行性变的发病机制中起着关键作用，最重要的是，明确了GFAP中的半胱氨酸 - 291可能是治疗INCL及其他潜在神经退行性疾病的一个有价值的药物靶点。
Significance This study reports that the intermediate filament protein GFAP is modified with protein palmitoylation. Increased GFAP expression and palmitoylation is involved in astrocyte proliferation and astrogliosis. We demonstrate that GFAP palmitoylation is regulated by PPT1, a palmitoylprotein thioesterase linked to a childhood neurodegenerative disorder, infantile neuronal ceroid lipofuscinosis. A palmitoylation-defective mutant of GFAP attenuates astrogliosis and the concurrent pathology in a loss-of-function PPT1 mouse. We conclude that accumulation of palmitoylated GFAP contributes to the pathogenesis of astrogliosis and neurodegeneration, suggesting that targeting the modified cysteine in GFAP may be a potential therapeutic strategy for the treatment of infantile neuronal ceroid lipofuscinosis and other neurodegenerative disorders. The homeostasis of protein palmitoylation and depalmitoylation is essential for proper physiological functions in various tissues, in particular the central nervous system (CNS). The dysfunction of PPT1 (PPT1-KI, infantile neuronal ceroid lipofuscinosis [INCL] mouse model), which catalyze the depalmitoylation process, results in serious neurodegeneration accompanied by severe astrogliosis in the brain. Endeavoring to determine critical factors that might account for the pathogenesis in CNS by palm-proteomics, glial fibrillary acidic protein (GFAP) was spotted, indicating that GFAP is probably palmitoylated. Questions concerning if GFAP is indeed palmitoylated in vivo and how palmitoylation of GFAP might participate in neural pathology remain unexplored and are waiting to be investigated. Here we show that GFAP is readily palmitoylated in vitro and in vivo; specifically, cysteine-291 is the unique palmitoylated residue in GFAP. Interestingly, it was found that palmitoylated GFAP promotes astrocyte proliferation in vitro. Furthermore, we showed that PPT1 depalmitoylates GFAP, and the level of palmitoylated GFAP is overwhelmingly up-regulated in PPT1-knockin mice, which lead us to speculate that the elevated level of palmitoylated GFAP might accelerate astrocyte proliferation in vivo and ultimately led to astrogliosis in INCL. Indeed, blocking palmitoylation by mutating cysteine-291 into alanine in GFAP attenuate astrogliosis, and remarkably, the concurrent neurodegenerative pathology in PPT1-knockin mice. Together, these findings demonstrate that hyperpalmitoylated GFAP plays critical roles in regulating the pathogenesis of astrogliosis and neurodegeneration in the CNS, and most importantly, pinpointing that cysteine-291 in GFAP might be a valuable pharmaceutical target for treating INCL and other potential neurodegenerative diseases.
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影响因子：
3.8
作者：
Lu JY;Hu J;Hofmann SL
通讯作者：
Hofmann SL
影响因子：
7.2
作者：
Hol, Elly M.;Capetanaki, Yassemi
通讯作者：
Capetanaki, Yassemi
影响因子：
4.8
作者：
Gottlieb, Colin D.;Zhang, Sheng;Linder, Maurine E.
通讯作者：
Linder, Maurine E.
影响因子：
7.7
作者：
Sadeghi RS;Kulej K;Kathayat RS;Garcia BA;Dickinson BC;Brady DC;Witze ES
通讯作者：
Witze ES
DOI：
10.1083/jcb.201008160
发表时间：
2010-12-27
期刊：
The Journal of cell biology
影响因子：
--
作者：
Salaun C;Greaves J;Chamberlain LH
通讯作者：
Chamberlain LH