CHRONIC SLEEP FRAGMENTATION ACCELERATES THE DEVELOPMENT OF PRODROMAL SYMPTOMS AND PATHOLOGICAL CHANGES IN PARKINSON’ S DISEASE MODEL MICE

Abstract Background Parkinson’ s disease (PD) is the second most common neurodegenerative disease after Alzheimer’ s disease. Patients with PD exhibit various non-motor symptoms, including constipation, hyposmia, and sleep disturbance, in addition to classical motor symptoms such as bradykinesia, muscular rigidity, and rest tremor. The pathological hallmarks of PD are phosphorylated alpha-synuclein (p-syn) accumulation and dopaminergic neuronal loss in substantia nigra pars compacta. Patients are generally diagnosed with PD after the onset of motor symptoms, but the onset of non-motor symptoms often precedes that of motor symptoms. This prodromal phase of PD, which lasts for more than a decade, is a critical time window for disease modification to prevent or delay the onset of motor symptoms. Insomnia is the most common sleep disorder in older adults and patients with PD. In patients with PD, chronic sleep fragmentation due to frequent nocturnal arousals is the most prevalent symptom of insomnia. While various PD-related etiologies induce chronic sleep fragmentation, recent epidemiological studies suggested that chronic sleep fragmentation itself may accelerate the clinical and pathological progression of PD. However, the precise causal relationship between progression of PD and chronic sleep fragmentation remains unknown. Aims & Objectives We aimed to test whether chronic sleep fragmentation accelerates the disease course of PD using model mice. Method Transgenic mouse model of PD (Tg) that recapitulates age-dependent onset and progression of premotor non-motor symptoms, or wild type (WT) mice were housed in either of the following cages from the age when Tg mice do not exhibit non-motor symptoms: (1) sleep disturbance (SD) cage, a running- wheel-based device that induces chronic sleep fragmentation similar to PD patients (SD group), (2) wheel cage (WC), a control cage with a running wheel but with no sleep disruption (WC group), or (3) normal cage (NC), another control cage without running wheel (NC group). After 5 or 6 weeks, multiple non- motor symptoms were evaluated. After 7 weeks, brains were collected, and p-syn accumulation in the brains of Tg mice was evaluated. Results Among Tg mice, only the SD group showed non-motor symptoms. Among WT mice, the SD group showed no or minimal non-motor symptoms which were milder than that of Tg mice in the SD group. Among Tg mice, the SD group showed significantly increased p-syn accumulation in multiple brain regions. Discussion & Conclusion These results suggest 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 potential target for preventing or delaying the motor onset of PD.