Motor-, behavior- and/or cognition-related symptoms are key hallmarks in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with TDP-43 pathology (FTLD-TDP), respectively. It has been reported that these patients also experience sleep disturbances, which might implicate a disturbed circadian rhythm of the sleep/wake cycle. It remains unknown, however, whether cells involved in the circadian sleep/wake cycle are affected by ALS- and FTLD-related neuropathological changes including phosphorylated TDP-43 (pTDP-43) aggregates and dipeptide repeat protein (DPR) inclusions resulting from the C9orf72 hexanucleotide repeat expansion. Immunohistochemistry for DPR and pTDP-43 pathology was performed in post-mortem hypothalamus and pineal gland tissue of patients with ALS and/or FTLD-TDP with and without the C9orf72 repeat expansion and healthy controls. Circadian sleep/wake-associated cells, including pinealocytes and hypothalamic neurons related to the suprachiasmatic nucleus (SCN), were microscopically assessed. We observed numerous DPR inclusions (poly(GA), poly(GP), poly(GR) and poly(PR)) in the pinealocytes and few poly(GA) inclusions in the SCN-related neurons in C9orf72-related ALS and/or FTLD-TDP cases. These circadian sleep/wake-associated cells, however, were devoid of pTDP-43 pathology both in C9orf72- and nonC9orf72-related ALS and/or FTLD-TDP cases. Our neuropathological findings show that pinealocytes and, to a lesser extent, SCN-related neurons are affected by DPR pathology. This may reflect an involvement of these cells in sleep/wake disturbances observed in ALS and/or FTLD-TDP patients.

中文翻译：

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昼夜节律性睡眠/苏醒相关细胞在C9orf72相关的ALS和FTLD病例中显示出二肽重复蛋白聚集体。

与运动，行为和/或认知有关的症状分别是患有肌萎缩性侧索硬化症（ALS）和额颞叶大叶变性（FTLD）且伴有TDP-43病理（FTLD-TDP）的患者的关键标志。据报道，这些患者还经历睡眠障碍，这可能暗示了睡眠/唤醒周期的昼夜节律紊乱。然而，尚不清楚参与昼夜睡眠/唤醒周期的细胞是否受ALS和FTLD相关的神经病理变化的影响，包括C9orf72产生的磷酸化TDP-43（pTDP-43）聚集体和二肽重复蛋白（DPR）内含物六核苷酸重复扩增。在患有和/或没有C9orf72重复扩增和健康对照的ALS和/或FTLD-TDP患者的下丘脑和松果体组织中进行DPR和pTDP-43病理学的免疫组织化学分析。显微镜评估了昼夜节律性睡眠/苏醒相关细胞，包括松果体细胞和与视交叉上核（SCN）相关的下丘脑神经元。我们在松果细胞中观察到许多DPR夹杂物（poly（GA），poly（GP），poly（GR）和poly（PR）），在C9orf72相关的ALS和/或SCN相关的神经元中几乎没有poly（GA）包含物FTLD-TDP案件。然而，这些昼夜节律性睡眠/苏醒相关细胞在C9orf72和非C9orf72相关的ALS和/或FTLD-TDP病例中都没有pTDP-43病理。我们的神经病理学发现表明，松果体细胞在较小程度上 SCN相关的神经元受DPR病理学影响。这可能反映出这些细胞参与了在ALS和/或FTLD-TDP患者中观察到的睡眠/唤醒障碍。