Brain and Mind Centre, University of Sydney, Sydney, New South Wales, Australia.
Faculty of Medicine and Health, School of Medical Sciences, University of Sydney, Camperdown, New South Wales, Australia.
J Neuropathol Exp Neurol. 2023 Aug 21;82(9):769-773. doi: 10.1093/jnen/nlad051.
The autophagy marker p62 appears as a consistent component of pathological aggregates in amyotrophic lateral sclerosis (ALS) and its modulation to facilitate protein degradation has been proposed as a potential therapeutic target. Importantly, recent studies have implicated diffuse phosphorylated TDP-43 inclusions that are immuno-negative for p62 in more rapid disease, highlighting the need for better understanding of p62 involvement in ALS pathogenesis. The present study set out to assess p62 pathology in the motor neurons of 31 patients with sporadic ALS that had either a short (<2 years) or longer (4-7 years) disease duration to determine its association with pTDP-43 pathology, motor neuron loss, and survival in sporadic disease. Our results identified significantly more cytoplasmic p62 aggregates in the spinal cord of patients with a shorter survival. Disease duration demonstrated a negative association with p62 burden and density of remaining motor neurons in the spinal cord, suggesting that survival in sporadic ALS is associated with the successful clearance of lower motor neurons with p62 aggregates. These findings implicate the autophagy pathway in ALS survival and provide support for further study of p62 as a potential prognostic biomarker in ALS.
自噬标记物 p62 作为肌萎缩侧索硬化症 (ALS) 中病理性聚集体的一致组成部分出现，其促进蛋白质降解的调节作用已被提出作为一种潜在的治疗靶点。重要的是，最近的研究表明，在疾病进展更快的情况下，弥漫性磷酸化 TDP-43 包含物对 p62 呈免疫阴性，这突出表明需要更好地了解 p62 在 ALS 发病机制中的作用。本研究旨在评估 31 例散发性 ALS 患者运动神经元中的 p62 病理学，这些患者的疾病持续时间较短（<2 年）或较长（4-7 年），以确定其与 pTDP-43 病理学、运动神经元丧失和散发性疾病中的存活之间的关系。我们的研究结果表明，在脊髓中，存活时间较短的患者的细胞质 p62 聚集体明显更多。疾病持续时间与 p62 负担和脊髓中剩余运动神经元的密度呈负相关，这表明在散发性 ALS 中，存活与成功清除具有 p62 聚集体的较低运动神经元有关。这些发现表明自噬途径与 ALS 的存活有关，并为进一步研究 p62 作为 ALS 的潜在预后生物标志物提供了支持。
