Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder caused by the loss of motor neurons from the brain and spinal cord. The ALS community has made remarkable strides over three decades by identifying novel familial mutations, generating animal models, elucidating molecular mechanisms, and ultimately developing promising new therapeutic approaches. Some of these approaches reduce the expression of mutant genes and are in human clinical trials, highlighting the need to carefully consider the normal functions of these genes and potential contribution of gene loss-of-function to ALS. Here, we highlight known loss-of-function mechanisms underlying ALS, potential consequences of lowering levels of gene products, and the need to consider both gain and loss of function to develop safe and effective therapeutic strategies.

肌萎缩侧索硬化 (ALS) 是一种致命的神经退行性疾病，由大脑和脊髓中运动神经元的丧失引起。通过识别新的家族突变、生成动物模型、阐明分子机制并最终开发出有希望的新治疗方法，ALS 社区在过去的三年中取得了显着的进步。其中一些方法减少了突变基因的表达，并且正在人体临床试验中，强调需要仔细考虑这些基因的正常功能以及基因功能丧失对 ALS 的潜在贡献。在这里，我们强调了 ALS 的已知功能丧失机制、降低基因产物水平的潜在后果，以及需要同时考虑功能的获得和丧失以制定安全有效的治疗策略。