Department of Pharmacology, Dong-A University College of Medicine, Busan, 49201, South Korea; Department of Translational Biomedical Sciences, Dong-A University College of Medicine, Busan, 49201, South Korea.
Department of Pharmacology, Dong-A University College of Medicine, Busan, 49201, South Korea; Neuroscience Translational Research Solution Center, Dong-A University College of Medicine, Busan, 49201, South Korea.
Biochem Biophys Res Commun. 2023 Nov 19;682:71-76. doi: 10.1016/j.bbrc.2023.09.092. Epub 2023 Sep 29.
Small heat shock proteins (sHSPs) are ATP-independent molecular chaperones with the α-crystalline domain that is critical to their chaperone activity. Within the sHSP family, three (HSPB1, HSPB3, and HSPB8) proteins are linked with inherited peripheral neuropathies, including distal hereditary motor neuropathy (dHMN) and Charco-Marie-Tooth disease (CMT). In this study, we introduced the HSPB3 Y118H (HSPB3) mutant gene identified from the CMT2 family in Drosophila. With a missense mutation on its α-crystalline domain, this human HSPB3 mutant gene induced a loss of motor activity accompanied by reduced mitochondrial membrane potential in fly neuronal tissues. Moreover, mitophagy, a critical mechanism of mitochondrial quality control, is downregulated in fly motor neurons expressing HSPB3. Surprisingly, PINK1 and Parkin, the core regulators of mitophagy, successfully rescued these motor and mitochondrial abnormalities in HSPB3 mutant flies. Results from the first animal model of HSPB3 mutations suggest that mitochondrial dysfunction plays a critical role in HSPB3-associated human pathology.
小分子热休克蛋白（sHSPs）是一种不依赖于 ATP 的分子伴侣，其α-晶状结构域对于其伴侣活性至关重要。在 sHSP 家族中，三种（HSPB1、HSPB3 和 HSPB8）蛋白与遗传性周围神经病有关，包括远端遗传性运动神经病（dHMN）和 Charco-Marie-Tooth 病（CMT）。在这项研究中，我们引入了从 CMT2 家族的果蝇中鉴定出的 HSPB3 Y118H（HSPB3）突变基因。由于其α-晶状结构域上的错义突变，这种人类 HSPB3 突变基因导致运动活性丧失，并伴有果蝇神经元组织中线粒体膜电位降低。此外，线粒体质量控制的关键机制——自噬，在表达 HSPB3 的果蝇运动神经元中下调。令人惊讶的是，PINK1 和 Parkin，自噬的核心调节因子，成功挽救了 HSPB3 突变果蝇的这些运动和线粒体异常。 HSPB3 突变的第一个动物模型的结果表明，线粒体功能障碍在 HSPB3 相关的人类病理学中起着关键作用。
