Department of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, CA, USA; Department of Neurology, Duke University School of Medicine, Durham, NC 27710, USA.
Department of Neurology, Duke University School of Medicine, Durham, NC 27710, USA.
Neurobiol Dis. 2023 Aug;184:106218. doi: 10.1016/j.nbd.2023.106218. Epub 2023 Jun 30.
In patients with amyotrophic lateral sclerosis (ALS), disease symptoms and pathology typically spread in a predictable spatiotemporal pattern beginning at a focal site of onset and progressing along defined neuroanatomical tracts. Like other neurodegenerative diseases, ALS is characterized by the presence of protein aggregates in postmortem patient tissue. Cytoplasmic, ubiquitin-positive aggregates of TDP-43 are observed in approximately 97% of sporadic and familial ALS patients, while SOD1 inclusions are likely specific to cases of SOD1-ALS. Additionally, the most common subtype of familial ALS, caused by a hexanucleotide repeat expansion in the first intron of the C9orf72 gene (C9-ALS), is further characterized by the presence of aggregated dipeptide repeat proteins (DPRs). As we will describe, cell-to-cell propagation of these pathological proteins tightly correlates with the contiguous spread of disease. While TDP-43 and SOD1 are capable of seeding protein misfolding and aggregation in a prion-like manner, C9orf72 DPRs appear to induce (and transmit) a 'disease state' more generally. Multiple mechanisms of intercellular transport have been described for all of these proteins, including anterograde and retrograde axonal transport, extracellular vesicle secretion, and macropinocytosis. In addition to neuron-to-neuron transmission, transmission of pathological proteins occurs between neurons and glia. Given that the spread of ALS disease pathology corresponds with the spread of symptoms in patients, the various mechanisms by which ALS-associated protein aggregates propagate through the central nervous system should be closely examined.
在肌萎缩侧索硬化症（ALS）患者中，疾病症状和病理通常以可预测的时空模式传播，从一个局灶性起始部位开始，并沿着特定的神经解剖途径进展。与其他神经退行性疾病一样，ALS 的特征是在尸检患者组织中存在蛋白质聚集体。细胞质中，TDP-43 的泛素阳性聚集体在大约 97%的散发性和家族性 ALS 患者中观察到，而 SOD1 包含物可能特异性存在于 SOD1-ALS 病例中。此外，最常见的家族性 ALS 亚型是由 C9orf72 基因第一内含子中的六核苷酸重复扩展引起的（C9-ALS），其特征进一步表现为聚集的二肽重复蛋白（DPR）的存在。正如我们将描述的那样，这些病理蛋白的细胞间传播与疾病的连续传播密切相关。虽然 TDP-43 和 SOD1 能够以类朊病毒的方式引发蛋白质错误折叠和聚集，但 C9orf72 DPR 似乎更普遍地诱导（和传递）“疾病状态”。已经描述了所有这些蛋白质的多种细胞间运输机制，包括顺行和逆行轴突运输、细胞外囊泡分泌和巨胞饮。除了神经元到神经元的传递外，病理蛋白还在神经元和神经胶质之间传递。鉴于 ALS 疾病病理学的传播与患者症状的传播相对应，应该仔细检查 ALS 相关蛋白聚集体通过中枢神经系统传播的各种机制。
