Parkinson's disease is a progressive neurodegenerative disease with well-documented motor symptoms as well as less recognised, but significant, non-motor symptoms. These non-motor symptoms include prodromal pain and peripheral neuropathy, the causes of which are unknown. We investigated the role of DJ-1/PARK7, a Parkinson's disease-associated gene, in prodromal pain and peripheral neuropathy. Using DJ-1 deficient mice, we conducted comprehensive sensory tests, cutaneous staining, molecular analyses and electrophysiological studies on mouse and human primary sensory neurons from dorsal root ganglia. We found that these mice exhibited cold hypersensitivity, oxidative stress, and neuropathy of the cutaneous fibres of primary sensory neurones before any motor impairments were observed. Mechanistically, DJ-1 in primary sensory neurones regulated this hypersensitivity and neuropathy via TRPA1 signalling. Interestingly, we discovered that DJ-1 also plays a role in the progression of chemotherapy-induced peripheral neuropathies. Pain and mechanisms associated with these neuropathies were exacerbated in DJ-1 deficient mice but were significantly reduced by the pharmacological activation of DJ-1. Importantly, we also confirmed the expression of DJ-1 and its therapeutic potential in human primary sensory neurons. Thus, we uncover a peripheral mechanism of DJ-1 and propose that it may serve as a new target for developing therapeutic approaches for Parkinson's disease-linked and other painful neuropathies.

中文翻译：

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帕金森病 DJ-1/PARK7 基因控制周围神经元兴奋性和疼痛性神经病变


帕金森病是一种进行性神经退行性疾病，具有有据可查的运动症状以及不太明显但重要的非运动症状。这些非运动症状包括前驱疼痛和周围神经病变，其原因尚不清楚。我们研究了帕金森病相关基因 DJ-1/PARK7 在前驱疼痛和周围神经病变中的作用。使用 DJ-1 缺陷小鼠，我们对小鼠和人类背根神经节的初级感觉神经元进行了全面的感觉测试、皮肤染色、分子分析和电生理研究。我们发现这些小鼠在观察到任何运动障碍之前表现出初级感觉神经元皮肤纤维的冷超敏反应、氧化应激和神经病变。从机制上讲，初级感觉神经元中的 DJ-1 通过 TRPA1 信号传导调节这种超敏反应和神经病变。有趣的是，我们发现 DJ-1 在化疗诱导的周围神经病变的进展中也起作用。与 DJ-1 缺陷小鼠相关的疼痛和机制加剧，但 DJ-1 的药理学激活显着减轻。重要的是，我们还证实了 DJ-1 的表达及其在人类初级感觉神经元中的治疗潜力。因此，我们揭示了 DJ-1 的外周机制，并提出它可能作为开发帕金森病相关和其他痛苦神经病治疗方法的新靶点。