HSP110 is a modulator of amyloid beta (Aβ) aggregation and proteotoxicity.

IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Journal of Neurochemistry Pub Date : 2024-08-23 DOI:10.1111/jnc.16214
Sabrina Montresor, Maria Lucia Pigazzini, Sudarson Baskaran, Mira Sleiman, Govinda Adhikari, Lukas Basilicata, Luca Secker, Natascha Jacob, Yara Ehlert, Anushree Kelkar, Gurleen Kaur Kalsi, Niraj Kulkarni, Paul Spellerberg, Janine Kirstein
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Abstract

Chaperones safeguard protein homeostasis by promoting folding and preventing aggregation. HSP110 is a cytosolic chaperone that functions as a nucleotide exchange factor for the HSP70 cycle. Together with HSP70 and a J-domain protein (JDP), HSP110 maintains protein folding and resolubilizes aggregates. Interestingly, HSP110 is vital for the HSP70/110/JDP-mediated disaggregation of amyloidogenic proteins implicated in neurodegenerative diseases (i.e., α-synuclein, HTT, and tau). However, despite its abundance, HSP110 remains still an enigmatic chaperone, and its functional spectrum is not very well understood. Of note, the disaggregation activity of neurodegenerative disease-associated amyloid fibrils showed both beneficial and detrimental outcomes in vivo. To gain a more comprehensive understanding of the chaperone HSP110 in vivo, we analyzed its role in neuronal proteostasis and neurodegeneration in C. elegans. Specifically, we investigated the role of HSP110 in the regulation of amyloid beta peptide (Aβ) aggregation using an established Aβ-C. elegans model that mimics Alzheimer's disease pathology. We generated a novel C. elegans model that over-expresses hsp-110 pan-neuronally, and we also depleted hsp-110 by RNAi-mediated knockdown. We assessed Aβ aggregation in vivo and in situ by fluorescence lifetime imaging. We found that hsp-110 over-expression exacerbated Aβ aggregation and appeared to reduce the conformational variability of the Aβ aggregates, whereas hsp-110 depletion reduced aggregation more significantly in the IL2 neurons, which marked the onset of Aβ aggregation. HSP-110 also plays a central role in growth and fertility as its over-expression compromises nematode physiology. In addition, we found that HSP-110 modulation affects the autophagy pathway. While hsp-110 over-expression impairs the autophagic flux, a depletion enhances it. Thus, HSP-110 regulates multiple nodes of the proteostasis network to control amyloid protein aggregation, disaggregation, and autophagic clearance.

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HSP110是淀粉样蛋白β(Aβ)聚集和蛋白毒性的调节剂。
伴侣蛋白通过促进折叠和防止聚集来保护蛋白质的平衡。HSP110 是一种细胞膜伴侣蛋白,是 HSP70 循环的核苷酸交换因子。HSP110 与 HSP70 和一种 J-结构域蛋白(JDP)共同维持蛋白质折叠并分解聚集体。有趣的是,HSP110 对于 HSP70/110/JDP 介导的与神经退行性疾病有关的淀粉样蛋白(即 α-突触核蛋白、HTT 和 tau)的分解至关重要。然而,尽管 HSP110 数量巨大,但它仍然是一种神秘的伴侣蛋白,其功能谱系也不甚明了。值得注意的是,神经退行性疾病相关淀粉样蛋白纤维的分解活性在体内既显示出有益的结果,也显示出有害的结果。为了更全面地了解体内伴侣蛋白 HSP110,我们分析了它在秀丽隐杆线虫神经元蛋白稳态和神经退行性变中的作用。具体来说,我们利用已建立的模拟阿尔茨海默病病理的 Aβ - elegans 模型,研究了 HSP110 在调节淀粉样 beta 肽(Aβ)聚集中的作用。我们生成了一种在泛神经元中过度表达 hsp-110 的新型 elegans 模型,并通过 RNAi- 介导的基因敲除技术耗尽了 hsp-110。我们通过荧光寿命成像评估了体内和原位的Aβ聚集。我们发现,hsp-110 的过度表达会加剧 Aβ 的聚集,并似乎会降低 Aβ 聚集的构象变异性,而 hsp-110 的耗竭则会更显著地降低 IL2 神经元的聚集,这标志着 Aβ 聚集的开始。HSP-110 在生长和繁殖中也起着核心作用,因为它的过度表达会损害线虫的生理机能。此外,我们还发现 HSP-110 的调节会影响自噬途径。HSP-110过度表达会损害自噬通量,而HSP-110缺乏则会增强自噬通量。因此,HSP-110调节蛋白稳态网络的多个节点,控制淀粉样蛋白的聚集、分解和自噬清除。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Neurochemistry
Journal of Neurochemistry 医学-神经科学
CiteScore
9.30
自引率
2.10%
发文量
181
审稿时长
2.2 months
期刊介绍: Journal of Neurochemistry focuses on molecular, cellular and biochemical aspects of the nervous system, the pathogenesis of neurological disorders and the development of disease specific biomarkers. It is devoted to the prompt publication of original findings of the highest scientific priority and value that provide novel mechanistic insights, represent a clear advance over previous studies and have the potential to generate exciting future research.
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