Lufrano Daniela, Gong Chunmei, Cecarini Valentina, Cuccioloni Massimiliano, Bonfili Laura, Sturaro Chiara, Bettegazzi Barbara, Ruzza Chiara, Perelló Mario, Angeletti Mauro, Eleuteri Anna Maria
School of Biosciences and Veterinary Medicine, University of Camerino, 62032, Camerino, Italy.
Departamento de Ciencias Biológicas, Facultad de Ciencias Exactas, Universidad Nacional La Plata (UNLP), CONICET, B1900 AVW, La Plata, Argentina.
Mol Neurobiol. 2025 Apr 26. doi: 10.1007/s12035-025-04976-5.
Protein homeostasis (proteostasis) is preserved by an orchestrated network of molecular mechanisms that regulate protein synthesis, folding, and degradation, ensuring cellular integrity and function. Proteostasis declines with age and is related to pathologies such as neurodegenerative diseases and cardiac disorders, which are accompanied by the accumulation of toxic protein aggregates. In this context, therapeutic strategies enhancing the two primary degradative systems involved in the cellular clearance of those abnormal proteins, namely ubiquitin-proteasome system and autophagy-lysosomal pathway, represent a promising approach to counteract the collapse of proteostasis in such pathological conditions. In this work, we explored the processing of ghrelin, a pleiotropic peptide hormone linked to energy metabolism and higher brain functions, which is reported to modulate the protein degradative mechanisms. According to our data, ghrelin is processed by serine hydrolases secreted into the conditioned medium of SH-SY5Y neuroblastoma cell line, commonly used in neurotoxicology and neuroscience research. Ghrelin processing leads to the formation of a shorter peptide (ghrelin(1-11)) that stimulates both the cell proteasome system and autophagy-lysosomal pathway, encompassing the selective autophagy of mitochondria. Our findings suggest that ghrelin processing may contribute to the maintenance of neuronal proteostasis.
蛋白质稳态（蛋白稳态）由一个精心编排的分子机制网络维持，该网络调节蛋白质的合成、折叠和降解，确保细胞的完整性和功能。蛋白稳态会随着年龄的增长而下降，并与神经退行性疾病和心脏疾病等病理状况相关，这些疾病伴随着有毒蛋白质聚集体的积累。在这种情况下，增强参与细胞清除这些异常蛋白质的两个主要降解系统（即泛素-蛋白酶体系统和自噬-溶酶体途径）的治疗策略，代表了一种在这种病理条件下对抗蛋白稳态崩溃的有前景的方法。在这项研究中，我们探索了胃饥饿素的加工过程，胃饥饿素是一种与能量代谢和高级脑功能相关的多效性肽激素，据报道它能调节蛋白质降解机制。根据我们的数据，胃饥饿素由分泌到SH-SY5Y神经母细胞瘤细胞系条件培养基中的丝氨酸水解酶进行加工，该细胞系常用于神经毒理学和神经科学研究。胃饥饿素的加工导致形成一种较短的肽（胃饥饿素(1 - 11)），它能刺激细胞蛋白酶体系统和自噬-溶酶体途径，包括线粒体的选择性自噬。我们的研究结果表明，胃饥饿素的加工可能有助于维持神经元的蛋白稳态。
