Department of Developmental Biology, Washington University Medical School Saint Louis, Saint Louis, MO, United States.
Needleman Center for Neurometabolism and Axonal Therapeutics, Washington University Medical School Saint Louis, MO, United States.
Pain. 2019 May;160 Suppl 1(Suppl 1):S17-S22. doi: 10.1097/j.pain.0000000000001528.
Peripheral neuropathy is the most common neurodegenerative disease affecting hundreds of millions of patients worldwide and is an important cause of chronic pain. Typical peripheral neuropathies are characterized by dysesthesias including numbness, crawling skin, a sensation of "pins and needles," and burning and stabbing pain. In addition, peripheral neuropathy can affect the motor and autonomic systems leading to symptoms such as weakness, constipation, and dysregulation of blood pressure. Peripheral neuropathies can be either hereditary or acquired and are a common consequence of diabetes and treatment with chemotherapy agents. Many neuropathies are due to degeneration of long axons; however, the mechanisms driving axon loss were unknown, and so no therapies are available to preserve vulnerable axons and prevent the development of peripheral neuropathy. With the recent identification of SARM1 as an injury-activated NADase enzyme that triggers axon degeneration, there is now a coherent picture emerging for the mechanism of axonal self-destruction. Here, we will present evidence that inhibiting the SARM1 pathway can prevent the development of peripheral neuropathy, describe the emerging mechanistic understanding of the axon degeneration program, and discuss how these mechanistic insights may be translated to the clinic for the prevention and treatment of peripheral neuropathy and other neurodegenerative disorders.
周围神经病变是影响全球数亿患者的最常见神经退行性疾病，也是慢性疼痛的重要原因。典型的周围神经病变的特征是感觉异常，包括麻木、爬行感、“刺痛”感以及灼痛和刺痛。此外，周围神经病变还会影响运动和自主神经系统，导致虚弱、便秘和血压失调等症状。周围神经病变可以是遗传性的，也可以是获得性的，是糖尿病和化疗药物治疗的常见后果。许多神经病变是由于长轴突的退化引起的；然而，导致轴突丧失的机制尚不清楚，因此没有可用的疗法来保护易损轴突并预防周围神经病变的发生。随着最近发现 SARM1 作为一种损伤激活的 NAD 酶，触发轴突退化，现在出现了一个连贯的轴突自我破坏的机制图。在这里，我们将提出证据表明，抑制 SARM1 途径可以预防周围神经病变的发生，描述轴突退化程序的新兴机制理解，并讨论这些机制见解如何转化为预防和治疗周围神经病变和其他神经退行性疾病的临床实践。
