Circadian disruption often arises prior to the onset of typical motor deficits in patients with Parkinson’s disease (PD). It remains unclear whether such a prevalent non-motor manifestation would contribute to the progression of PD. Diffusible oligomeric alpha-synuclein (O-αSyn) is perceived as the most toxic and rapid-transmitted species in the early stages of PD. Exploring the factors that influence the spread and toxicity of O-αSyn should be helpful for developing effective interventions for the disease. The aim of this study was to explore the effects of circadian disruption on PD pathology and parkinsonism-like behaviors in a novel mouse model induced by O-αSyn. We discovered that O-αSyn could enter the brain rapidly following intranasal administration, resulting in the formation of nitrated-αSyn pathology and non-motor symptoms of the mice. Meanwhile, circadian disruption exacerbated the burden of nitrated-αSyn pathology and accelerated the loss of dopaminergic neurons in O-αSyn-treated mice. Subsequent experiments demonstrated that circadian disruption might act via promoting nitrative stress and neuroinflammation. These findings could highlight the circadian rhythms as a potential diagnostic and therapeutic target in early-stage PD.

帕金森病 (PD) 患者通常在出现典型运动缺陷之前就出现昼夜节律紊乱。目前尚不清楚这种普遍的非运动表现是否会导致帕金森病的进展。扩散性寡聚 α-突触核蛋白 (O-αSyn) 被认为是 PD 早期阶段毒性最强、传播速度最快的物种。探索影响 O-αSyn 传播和毒性的因素应该有助于制定针对该疾病的有效干预措施。本研究的目的是探讨昼夜节律紊乱对 O-αSyn 诱导的新型小鼠模型中 PD 病理学和帕金森病样行为的影响。我们发现O-αSyn鼻内给药后可迅速进入大脑，导致小鼠硝化-αSyn病理和非运动症状的形成。与此同时，昼夜节律紊乱加剧了硝化-αSyn 病理学的负担，并加速了 O-αSyn 治疗小鼠多巴胺能神经元的损失。随后的实验表明，昼夜节律紊乱可能通过促进硝化应激和神经炎症来发挥作用。这些发现可以强调昼夜节律作为早期帕金森病的潜在诊断和治疗目标。