Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), c/Nicolás Cabrera, 1. Universidad Autónoma de Madrid, Cantoblanco, 28049, Madrid, Spain.
Department of Neuropathology and Tissue Bank, Unidad de Investigación Proyecto Alzheimer, Fundación CIEN, Instituto de Salud Carlos III, Madrid, Spain.
Neurobiol Dis. 2017 Dec;108:249-260. doi: 10.1016/j.nbd.2017.09.001. Epub 2017 Sep 6.
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease and the main cause of motor neuron pathology. The etiology of the disease remains unknown, and no effective therapy exists to halt the disease or improve the quality of life. Here, we provide compelling evidence for the existence of fungal infection in ALS. Immunohistochemistry analysis using a battery of antifungal antibodies revealed fungal structures such as yeast and hyphae in the motor cortex, the medulla and the spinal cord, in eleven patients with ALS. Some fungal structures were localized intracellularly and even intranuclearly, indicating that this infection is not the result of post-mortem colonization. By contrast, this burden of fungal infection cannot be observed in several CNS areas of control subjects. PCR analysis and next generation sequencing of DNA extracted from frozen neural tissue identified a variety of fungal genera including Candida, Malassezia, Fusarium, Botrytis, Trichoderma and Cryptococcus. Overall, our present observations provide strong evidence for mixed fungal infections in ALS patients. The exact mixed infection varies from patient to patient consistent with the different evolution and severity of symptoms in each ALS patient. These novel findings provide a logical explanation for the neuropathological observations of this disease, such as neuroinflammation and elevated chitinase levels, and could help to implement appropriate therapies.
肌萎缩侧索硬化症（ALS）是一种破坏性的神经退行性疾病，是运动神经元病理的主要原因。该疾病的病因仍不清楚，也没有有效的治疗方法可以阻止疾病的发展或提高生活质量。在这里，我们提供了令人信服的证据，证明 ALS 中存在真菌感染。使用一系列抗真菌抗体的免疫组织化学分析显示，在 11 名 ALS 患者的运动皮层、延髓和脊髓中存在真菌结构，如酵母和菌丝。一些真菌结构定位于细胞内，甚至核内，表明这种感染不是死后定植的结果。相比之下，在几个对照受试者的中枢神经系统区域中，不能观察到这种真菌感染的负担。从冷冻神经组织中提取的 DNA 的 PCR 分析和下一代测序鉴定出多种真菌属，包括假丝酵母属、糠秕马拉色菌属、镰刀菌属、Botrytis、木霉属和隐球菌属。总的来说，我们目前的观察结果为 ALS 患者的混合真菌感染提供了有力的证据。确切的混合感染因患者而异，与每个 ALS 患者症状的不同演变和严重程度一致。这些新发现为该疾病的神经病理学观察结果提供了合理的解释，例如神经炎症和壳聚糖酶水平升高，并可能有助于实施适当的治疗。
