Identification of DARPP-32 as a novel sleep regulator in physiological conditions and experimental Parkinsonism
Clarissa Anna Pisanò, Maria Laura Santino, Alice Russotto, Gilberto Fisone
TL;DR
This study shows that DARPP-32, a protein in brain cells, plays a key role in regulating sleep and could help treat sleep issues in Parkinson’s disease.
Contribution
DARPP-32 is identified as a novel, cell-specific regulator of sleep and a potential therapeutic target for Parkinson’s-related excessive daytime sleepiness.
Findings
DARPP-32 deletion in D2R/A2AR-expressing neurons reduces NREM sleep and counteracts excessive daytime sleepiness in Parkinsonism.
DARPP-32 loss in D1R neurons increases NREM sleep stability during the inactive phase.
Sleep fragmentation in Parkinsonism is not improved by DARPP-32 deletion in D1R neurons.
Abstract
Sleep disorders are common in Parkinson’s disease (PD) and respond poorly to current pharmacological treatments, partly due to limited understanding of their underlying mechanisms. Using polysomnographic recordings, we investigated the role of dopamine- and cAMP-regulated phosphoprotein 32 kDa (DARPP-32) in sleep-wake regulation and PD-related sleep dysfunction. In naive mice, the selective ablation of DARPP-32 in striatal projection neurons (SPN) co-expressing dopamine D2 and adenosine A2A receptors reduced NREM sleep during the active phase of the circadian cycle, whereas its deletion in dopamine D1 receptor-expressing SPN increased NREM sleep stability during the inactive phase. In a mouse model of PD, excessive daytime sleepiness (EDS), a common non-motor symptom in PD, was abolished by DARPP-32 deletion in D2R/A2AR-expressing SPN but not in D1R-expressing SPN, which also failed to…
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Taxonomy
TopicsParkinson's Disease Mechanisms and Treatments · Sleep and Wakefulness Research · Nuclear Receptors and Signaling