Department of Biological Sciences, Centre for the Neurobiology of Stress, University of Toronto Scarborough, Toronto, Ontario, Canada.
J Alzheimers Dis. 2018;66(3):1295-1308. doi: 10.3233/JAD-180536.
HSPA6 (Hsp70B') is an inducible member of the Hsp70 (HSPA) family of heat shock proteins that is present in the human genome and not found in mouse and rat. Hence it is lacking in current animal models of neurodegenerative diseases. To advance knowledge of the little studied HSPA6, differentiated human neuronal SH-SY5Y cells were treated with the proteotoxic stress-inducing agent MG132. A robust induction of HSPA6 was apparent which localized to the periphery of MG132-induced protein aggregates in the neuronal cytoplasm. Components of the protein disaggregation/refolding machine that co-operate with Hsp70 also targeted the periphery of cytoplasmic protein aggregates, including DNAJB1 (Hsp40-1), HSPH1 (Hsp105α), and HSPB1 (Hsp27). These data suggest that HSPA6 is involved in the response of human neuronal cells to proteotoxic stress that is a feature of neurodegenerative diseases which have been characterized as protein misfolding disorders. Constitutively expressed HSPA8 (Hsc70) also localized tothe periphery of cytoplasmic protein aggregates following the treatment of differentiated human neuronal cells with MG132. HSPA8 could provide a rapid response to proteotoxic stress in neuronal cells, circumventing the time required to upregulate inducible Hsps.
HSPA6（Hsp70B'）是热休克蛋白（HSPA）家族中一种可诱导的成员，存在于人类基因组中，而在小鼠和大鼠中未发现。因此，它在当前神经退行性疾病的动物模型中缺失。为了深入了解研究较少的 HSPA6，用蛋白毒性应激诱导剂 MG132 处理分化的人神经元 SH-SY5Y 细胞。明显诱导出 HSPA6，其定位于神经元细胞质中 MG132 诱导的蛋白质聚集体的外围。与 Hsp70 合作的蛋白质解聚/重折叠机器的组件也靶向细胞质蛋白质聚集体的外围，包括 DNAJB1（Hsp40-1）、HSPH1（Hsp105α）和 HSPB1（Hsp27）。这些数据表明，HSPA6 参与人类神经元细胞对蛋白毒性应激的反应，这是神经退行性疾病的特征，这些疾病已被表征为蛋白质错误折叠疾病。在用 MG132 处理分化的人神经元细胞后，组成型表达的 HSPA8（Hsc70）也定位于细胞质蛋白质聚集体的外围。HSPA8 可以为神经元细胞的蛋白毒性应激提供快速反应，避免上调诱导型 Hsps 所需的时间。
