散发性ALS患者的淋巴细胞中HSC70表达降低,并有助于TDP-43的积累

IF 2.5 4区 医学 Q2 CLINICAL NEUROLOGY Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration Pub Date : 2020-01-02 DOI:10.1080/21678421.2019.1672749
A. Arosio, R. Cristofani, O. Pansarasa, V. Crippa, C. Riva, R. Sirtori, V. Menendez, N. Riva, F. Gerardi, C. Lunetta, Cristina Cereda, A. Poletti, C. Ferrarese, L. Tremolizzo, G. Sala
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引用次数: 23

摘要

摘要目的:伴侣介导的自噬(CMA)有助于TDP-43的降解,TDP-43是散发性肌萎缩侧索硬化症(sALS)患者运动神经元中常见的细胞质内含物的主要成分,这表明CMA可能参与聚集体的形成。为了探索这种可能性,在本研究中,我们验证了sALS患者可能存在的系统性CMA改变及其对TDP-43表达的影响。材料和方法:在来自30名sALS患者和30名健康对照的外周血单核细胞(PBMC)中,评估了CMA的两种关键介质胞质伴侣HSC70和溶酶体受体LAMP2A的基因和蛋白质表达。还分析了TDP-43和共伴侣BAG1和BAG3的表达。结果:我们发现患者细胞中HSC70的表达减少,LAMP2A没有变化,不溶性TDP-43蛋白水平增加,细胞内定位异常。我们还观察到共伴侣BAG1和BAG3的不平衡表达。HSC70下调在来源于散发性和TARDBP突变ALS患者的永生淋巴母细胞系中得到证实。最后,我们证明HSC70沉默直接增加了人类神经母细胞瘤细胞中TDP-43蛋白水平。讨论:我们的研究结果不支持sALS患者存在系统性CMA改变,但表明HSC70改变直接参与了ALS的发病机制。
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HSC70 expression is reduced in lymphomonocytes of sporadic ALS patients and contributes to TDP-43 accumulation
Abstract Aim: The demonstration that chaperone-mediated autophagy (CMA) contributes to the degradation of TDP-43, the main constituent of cytoplasmic inclusions typically found in motor neurons of patients with sporadic amyotrophic lateral sclerosis (sALS), has pointed out a possible involvement of CMA in aggregate formation. To explore this possibility, in this study, we verified the presence of a possible systemic CMA alteration in sALS patients and its effect on TDP-43 expression. Materials and methods: Gene and protein expression of the cytosolic chaperone HSC70 and the lysosome receptor LAMP2A, the two pivotal mediators of CMA, was assessed in peripheral blood mononuclear cells (PBMCs) derived from 30 sALS patients and 30 healthy controls. The expression of TDP-43 and co-chaperones BAG1 and BAG3 was also analyzed. Results: We found reduced HSC70 expression in patient cells, with no change in LAMP2A, and increased insoluble TDP-43 protein levels, with an aberrant intracellular localization. We also observed an unbalanced expression of co-chaperones BAG1 and BAG3. HSC70 down-regulation was confirmed in immortalized lymphoblastoid cell lines derived from sporadic and TARDBP mutant ALS patients. Lastly, we demonstrated that HSC70 silencing directly increases TDP-43 protein levels in human neuroblastoma cells. Discussion: Our results do not support the existence of a systemic CMA alteration in sALS patients but indicate a direct involvement of HSC70 alterations in ALS pathogenesis.
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来源期刊
CiteScore
5.40
自引率
10.70%
发文量
64
期刊介绍: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration is an exciting new initiative. It represents a timely expansion of the journal Amyotrophic Lateral Sclerosis in response to the clinical, imaging pathological and genetic overlap between ALS and frontotemporal dementia. The expanded journal provides outstanding coverage of research in a wide range of issues related to motor neuron diseases, especially ALS (Lou Gehrig’s disease) and cognitive decline associated with frontotemporal degeneration. The journal also covers related disorders of the neuroaxis when relevant to these core conditions.
期刊最新文献
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