Inami Sho, Jenny Benjamin P, Akpoghiran Oghenerukevwe, Gallagher Sara I, Strich Alexandra K, Tonoki Ayako, Trotti Davide, Haeusler Aaron R, Koh Kyunghee
Department of Neuroscience, The Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, USA. 19107.
Department of Biochemistry, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan.
bioRxiv. 2025 Aug 11:2025.08.07.669085. doi: 10.1101/2025.08.07.669085.
Circadian rhythm disruptions are common across neurodegenerative diseases, but their link to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) remains unclear. The hexanucleotide repeat expansion is the most prevalent genetic cause of ALS/FTD. Here, we used models expressing toxic arginine-rich dipeptides (PR or GR) or GGGGCC hexanucleotide repeats to investigate circadian deficits in C9orf72-ALS/FTD. We found that circadian rhythmicity and period length were disrupted in a repeat number-, dosage-, and age-dependent manner. Additionally, we observed lower levels of the neuropeptide PDF, a key regulator of free-running circadian rhythms, as well as decreased projection complexity and reduced neuronal activity in PDF-expressing neurons. Importantly, increases in neuronal activity significantly restored circadian function under select conditions. These results implicate reduced neuronal activity in C9orf72-ALS/FTD circadian deficits, underscoring the importance of precisely tuned, circuit- and stage-specific interventions.
昼夜节律紊乱在神经退行性疾病中很常见，但其与肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）的联系仍不清楚。六核苷酸重复扩增是ALS/FTD最常见的遗传病因。在此，我们使用表达有毒富含精氨酸二肽（PR或GR）或GGGGCC六核苷酸重复序列的模型来研究C9orf72-ALS/FTD中的昼夜节律缺陷。我们发现昼夜节律性和周期长度以重复次数、剂量和年龄依赖的方式受到破坏。此外，我们观察到神经肽PDF（自由运行昼夜节律的关键调节因子）水平较低，以及表达PDF的神经元的投射复杂性降低和神经元活动减少。重要的是，在特定条件下，神经元活动的增加显著恢复了昼夜节律功能。这些结果表明C9orf72-ALS/FTD昼夜节律缺陷中神经元活动减少，强调了精确调整的、针对特定回路和阶段的干预措施的重要性。
