Pradhan Raj Kumar, Kinney Nikolas G, Jensen Brigid K, Ilieva Hristelina
Jefferson Weinberg ALS Center, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, JHN 4th Floor Suite 400, Philadelphia, PA 19107, USA.
Neurol Int. 2025 May 9;17(5):73. doi: 10.3390/neurolint17050073.
Neuropathy is a debilitating disorder characterized by peripheral nerve dysfunction and damage to sensory, motor, and autonomic neurons and their axons. While homozygous mutations in DNAJB2/HSJ1 have been linked to early-onset neuropathy, a heterozygous DNAJB2 c.823+6C>T was discovered in an adult patient with severe sensory-motor polyneuropathy. This mutation is predicted to affect both isoforms of the protein. DNAJB2 (HSP40), a key member of the heat shock protein family, plays a critical role in cellular protection and stress, including response to heat shock. DNAJB2 traffics unfolded proteins to another heat shock protein, HSP70, and activates its ATPase activity to result in a correctly folded protein(s). In this study, we aimed to investigate the effects of the heterozygous DNAJB2 c.823+6C>T mutation on the stress response of DNAJB2 in fibroblasts obtained from the neuropathy patient. The fibroblasts were subjected to one hour of heat shock at 42 °C, and the time course of expression levels of DNAJB2 was established. Additionally, we evaluated the therapeutic efficacy of Cystamine, which has been shown to modulate DNAJB2 levels in cellular and animal models of Huntington's disease. Our results revealed reduced baseline levels of DNAJB2 between the mutant and control fibroblasts. Importantly the mutant cells exhibited a diminished response to heat shock. Thus, the mutation affects the upregulation of DNAJB2 under stress, possibly contributing to the pathogenesis of sensory-motor polyneuropathy. A 48-h pretreatment with 150 μM of Cystamine increased the levels of DNAJB2 in both the control and patient's fibroblasts. To the best of our knowledge, this is the first study to explore this mutant form of DNAJB2 in neuropathy. The study demonstrated that the heterozygous DNAJB2 c.823+6C>T mutation leads to impaired DNAJB2 response to heat shock in the fibroblasts. Cystamine showed promise in restoring DNAJB2 expression, highlighting the need for further research into targeted therapeutic strategies for DNAJB2-related disorders.
神经病变是一种使人衰弱的疾病，其特征为周围神经功能障碍以及感觉神经元、运动神经元和自主神经元及其轴突受损。虽然DNAJB2/HSJ1的纯合突变与早发性神经病变有关，但在一名患有严重感觉运动性多发性神经病变的成年患者中发现了杂合的DNAJB2 c.823+6C>T突变。预计该突变会影响该蛋白质的两种同工型。DNAJB2（热休克蛋白40）是热休克蛋白家族的关键成员，在细胞保护和应激（包括对热休克的反应）中起关键作用。DNAJB2将未折叠的蛋白质转运至另一种热休克蛋白HSP70，并激活其ATP酶活性，以产生正确折叠的蛋白质。在本研究中，我们旨在研究杂合的DNAJB2 c.823+6C>T突变对从该神经病变患者获取的成纤维细胞中DNAJB2应激反应的影响。将这些成纤维细胞在42℃下进行1小时的热休克处理，并确定DNAJB2表达水平的时间进程。此外，我们评估了胱胺的治疗效果，在亨廷顿舞蹈病的细胞和动物模型中，胱胺已被证明可调节DNAJB2水平。我们的结果显示，突变型和成纤维细胞对照之间的DNAJB2基线水平降低。重要的是，突变细胞对热休克的反应减弱。因此，该突变影响应激状态下DNAJB2的上调，可能导致感觉运动性多发性神经病变的发病机制。用150μM胱胺进行48小时预处理可增加对照和成纤维细胞患者细胞中DNAJB2的水平。据我们所知，这是第一项在神经病变中探索这种DNAJB2突变形式的研究。该研究表明，杂合的DNAJB2 c.823+6C>T突变导致成纤维细胞中DNAJB2对热休克的反应受损。胱胺在恢复DNAJB2表达方面显示出前景，突出了对DNAJB相关疾病的靶向治疗策略进行进一步研究的必要性。
