Objective: To investigate the molecular mechanisms by which chronic sleep fragmentation accelerates the progression of prodromal Parkinson’s disease (PD).

Background: Recent epidemiological studies suggest that chronic sleep fragmentation is not only a non-motor symptom of PD but may also accelerate PD progression. Using a prodromal PD mouse model, A53T SNCA bacterial artificial chromosome transgenic (Tg) mice, we previously showed that chronic sleep fragmentation accelerates the onset of hyposmia and constipation and exacerbates α-synuclein pathology and dopaminergic cell loss. Elucidating the underlying molecular mechanisms may help identify novel therapeutic strategies, considering that the prodromal phase represents a critical window for disease modification.

Method: Tg and wild-type (WT) mice (10–11 weeks old) were assigned to either (1) a Sleep Disturbance (SD) group: housed in an SD cage, a running-wheel-based device that induces chronic sleep fragmentation similar to that seen in PD patients, or (2) a Wheel Cage (WC) group: housed in a control cage with a running wheel but without sleep disruption. After 6 weeks, sufficient to accelerate prodromal symptom onset and neuropathology in our prior work, brains and biofluids (cerebrospinal fluid and plasma) were collected. The cerebral cortex was subjected to bulk RNA-seq analysis, and biofluids were subjected to proteomic analysis.

Results: Brain transcriptomic analysis identified 59 differentially expressed genes (DEGs) between the SD and WC groups in Tg mice (|fold change| > 1.25, p < 0.01). Pathway analysis showed significant enrichment of multiple biological pathways associated with neurodegenerative diseases, including but not limited to PD. These alterations were absent in WT mice, suggesting that chronic sleep fragmentation differently affects mice with or without the underlying prodromal PD. Intriguingly, the biological pathway primarily altered in the brain transcriptome and biofluid proteome overlapped, raising the possibility that brain molecular changes may be reflected in, or detectable through, biofluids.

Conclusion: Chronic sleep fragmentation modulates molecular pathomechanisms in both the brain and biofluids in a prodromal PD mouse model. These findings provide insight to potential strategies to delay or prevent the motor onset of PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/multi-omics-analysis-reveals-brain-and-biofluid-molecular-changes-induced-by-chronic-sleep-fragmentation-in-a-prodromal-parkinsons-disease-mouse-model/