Objective: To investigate whether chronic sleep fragmentation accelerates the onset of prodromal symptoms and pathology of Parkinson’s disease (PD) in mice.

Background: The prodromal phase of PD, which lasts over a decade, is a crucial time window for disease modification. Insomnia is the most common sleep disorder in older adults and patients with PD. The primary symptom of insomnia in patients with PD is frequent nocturnal arousal, leading to sleep fragmentation. While chronic sleep fragmentation was conventionally considered a consequence of PD progression, recent epidemiological studies suggested that chronic sleep fragmentation could exacerbate PD progression. However, their precise causal relationship remains elusive.

Method: A53T SNCA bacterial artificial chromosome transgenic (Tg) mice, a PD model that recapitulates prodromal symptoms and brain pathology, and wild-type (WT) mice were used. Mice were assigned to either of the following three groups at 10-11 weeks of age when the Tg mice have not yet developed prodromal symptoms: (1) Sleep Disturbance (SD) group: housing the mice in the SD cage, a running-wheel-based device that induces chronic sleep fragmentation similar to PD patients, (2) Wheel Cage (WC) group: housing the mice in the WC, a control cage with a running wheel but with no sleep disruption, or (3) Normal Cage (NC) group: housing the mice in the NC, another control cage without running wheel. After 5 or 6 weeks, constipation or hyposmia was evaluated, respectively. After 7 weeks, phosphorylated α-synuclein (p-syn) accumulation in the brains was evaluated.

Results: Among the Tg mice, only the SD group showed constipation and hyposmia. Among WT mice, the SD group mice showed no hyposmia; they showed mild constipation, which was milder than that of the Tg mice in the SD group. Among the Tg mice, proteinase K (PK)-resistant p-syn was significantly increased in the hippocampus and piriform cortex in the SD group. In addition, the severity of PK-resistant p-syn accumulation positively correlated with the severity of chronic sleep fragmentation.

Conclusion: These results demonstrate that chronic sleep fragmentation accelerates the onset of prodromal symptoms and p-syn accumulation in PD model mice. Our findings implicate that chronic sleep fragmentation would be a novel target to prevent or delay the motor onset of PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/chronic-sleep-fragmentation-accelerates-the-onset-of-prodromal-symptoms-and-pathology-in-parkinsons-disease-model-mice/