Montresor Sabrina, Pigazzini Maria Lucia, Baskaran Sudarson, Sleiman Mira, Adhikari Govinda, Basilicata Lukas, Secker Luca, Jacob Natascha, Ehlert Yara, Kelkar Anushree, Kalsi Gurleen Kaur, Kulkarni Niraj, Spellerberg Paul, Kirstein Janine
Department of Cell Biology, University of Bremen, Bremen, Germany.
Leibniz Institute for Molecular Pharmacology, Berlin, Germany.
J Neurochem. 2025 Jan;169(1):e16214. doi: 10.1111/jnc.16214. Epub 2024 Aug 23.
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.
伴侣蛋白通过促进蛋白质折叠和防止聚集来维护蛋白质稳态。HSP110是一种胞质伴侣蛋白，作为HSP70循环的核苷酸交换因子发挥作用。HSP110与HSP70和一种J结构域蛋白（JDP）一起，维持蛋白质折叠并使聚集物重新溶解。有趣的是，HSP110对于HSP70/110/JDP介导的与神经退行性疾病相关的淀粉样蛋白（即α-突触核蛋白、亨廷顿蛋白和tau蛋白）的解聚至关重要。然而，尽管HSP110含量丰富，但它仍然是一种神秘的伴侣蛋白，其功能谱尚未得到很好的理解。值得注意的是，与神经退行性疾病相关的淀粉样原纤维的解聚活性在体内显示出既有有益的结果也有有害的结果。为了更全面地了解伴侣蛋白HSP110在体内的作用，我们分析了它在秀丽隐杆线虫神经元蛋白质稳态和神经退行性变中的作用。具体而言，我们使用一个模拟阿尔茨海默病病理的既定Aβ-秀丽隐杆线虫模型，研究了HSP110在调节淀粉样β肽（Aβ）聚集方面的作用。我们构建了一个在全神经元中过表达hsp-110的新型秀丽隐杆线虫模型，并且我们还通过RNAi介导的敲低来耗尽hsp-110。我们通过荧光寿命成像在体内和原位评估Aβ聚集情况。我们发现hsp-110的过表达加剧了Aβ聚集，并且似乎降低了Aβ聚集体的构象变异性，而hsp-110的耗尽在标记Aβ聚集起始的IL2神经元中更显著地减少了聚集。HSP-110在生长和生育能力方面也起着核心作用，因为它的过表达会损害线虫的生理功能。此外，我们发现HSP-110的调节会影响自噬途径。虽然hsp-110的过表达会损害自噬通量，但耗尽它则会增强自噬通量。因此，HSP-110调节蛋白质稳态网络的多个节点，以控制淀粉样蛋白的聚集、解聚和自噬清除。
