Nadais André, Martins Inês, Henriques Ana Gabriela, Trigo Diogo, da Cruz E Silva Odete A B
Neurosciences and Signaling Group, Department of Medical Sciences, Institute of Biomedicine, University of Aveiro, 3810-193, Aveiro, Portugal.
Cell Mol Neurobiol. 2025 Mar 13;45(1):24. doi: 10.1007/s10571-025-01539-z.
Protein aggregation is remarkably associated with several neuropathologies, including Alzheimer´s (AD) and Parkinson´s disease (PD). The first is characterized by hyperphosphorylated tau protein and Aβ peptide deposition, thus forming intracellular neurofibrillary tangles and extracellular senile plaques, respectively; while, in PD, α-synuclein aggregates and deposits as Lewy bodies. Considerable research has focused on developing protein aggregation models to be explored as research tools. In the present work, four in vitro models for studying protein aggregation were studied and compared, namely treatment with: the toxic Aβ1-42 peptide, the isoflavone rotenone, the ATP synthase inhibitor oligomycin, and the proteosome inhibitor MG-132. All treatments result in aggregation-relevant events in the human neural SH-SY5Y cell line, but significant model-dependent differences were observed. In terms of promoting aggregate formation, Aβ and MG-132 provoked the greatest effect, but only MG-132 was associated with an increase in HSP-70 chaperone expression. In fact, the type of aggregates formed appear to be dependent on the treatment employed, and supports the hypothesis that Aβ exposure is a relevant AD model, and rotenone is a valid model for PD. Furthermore, the results revealed that protein phosphorylation is relevant to aggregate formation and as expected, tau co-localized to the deposits formed in the Aβ peptide aggregate induction cell model. In summary, different molecular processes, from overall and specific protein aggregation to proteostatic modulation, can be induced by using distinct aggregation modelling strategies, and these can be used to study different protein-aggregation-related processes associated with distinct neuropathologies.
蛋白质聚集与多种神经病理学显著相关，包括阿尔茨海默病（AD）和帕金森病（PD）。前者的特征是tau蛋白过度磷酸化和Aβ肽沉积，从而分别形成细胞内神经原纤维缠结和细胞外老年斑；而在PD中，α-突触核蛋白聚集并沉积为路易小体。大量研究集中在开发蛋白质聚集模型作为研究工具。在本研究中，对四种用于研究蛋白质聚集的体外模型进行了研究和比较，即分别用有毒的Aβ1-42肽、异黄酮鱼藤酮、ATP合酶抑制剂寡霉素和蛋白酶体抑制剂MG-132处理。所有处理均在人神经SH-SY5Y细胞系中引发了与聚集相关的事件，但观察到了显著的模型依赖性差异。在促进聚集体形成方面，Aβ和MG-132的作用最大，但只有MG-132与热休克蛋白70（HSP-70）伴侣蛋白表达增加有关。事实上，形成的聚集体类型似乎取决于所采用的处理方式，这支持了Aβ暴露是一种相关AD模型、鱼藤酮是一种有效PD模型的假设。此外，结果表明蛋白质磷酸化与聚集体形成相关，正如预期的那样，tau与在Aβ肽聚集诱导细胞模型中形成的沉积物共定位。总之，通过使用不同的聚集建模策略可以诱导从整体和特定蛋白质聚集到蛋白质稳态调节的不同分子过程，这些过程可用于研究与不同神经病理学相关的不同蛋白质聚集相关过程。
