Abstract
Sleep disturbances co-occur with and precede the onset of motor symptoms in Parkinson's disease (PD). We evaluated sleep fragmentation and thalamocortical sleep spindles in mice expressing the p.G2019S mutation of the leucine-rich repeat kinase 2 (LRRK2) gene, one of the most common genetic forms of PD. Thalamocortical sleep spindles are oscillatory events that occur during slow-wave sleep that are involved in memory consolidation. We acquired data from electrocorticography, sleep behavioral measures, and a rotarod-based motor enrichment task in 28 LRRK2-G2019S knock-in mice and 27 wild-type controls (8–10 month-old males). Sleep was more fragmented in LRRK2-G2019S mice; sleep bouts were shorter and more numerous, even though total sleep time was similar to controls. LRRK2-G2019S animals expressed more sleep spindles, and individual spindles were longer in duration than in controls. We then chronically administered the LRRK2-inhibitor MLi-2 in-diet to n = 12 LRRK2-G2019S and n = 15 wild-type mice for a within-subject analysis of the effects of kinase inhibition on sleep behavior and physiology. Treatment with MLi-2 did not impact these measures. The data indicate that the LRRK2-G2019S mutation could lead to reduced sleep quality and altered sleep spindle physiology. This suggests that sleep spindles in LRRK2-G2019S animals could serve as biomarkers for underlying alterations in sleep networks resulting from the LRRK2-G2019S mutation, and further evaluation in human LRRK2-G2019S carriers is therefore warranted.
Highlights
Mutations of the leucine-rich repeat kinase-2 (LRRK2) gene represent one of the most common genetic causes of Parkinson’s disease (PD) [1]
As with idiopathic PD, LRRK2 PD is associated with the progressive loss of dopaminergic neurons in the substantia nigra pars compacta that results in debilitating motor symptoms such as bradykinesia, rigidity, and tremor
Sleep disturbances and sleepassociated neurophysiology have been studied in idiopathic PD, much less is known about how sleep is altered in LRRK2 PD, during the prodromal period
Summary
Mutations of the leucine-rich repeat kinase-2 (LRRK2) gene represent one of the most common genetic causes of Parkinson’s disease (PD) [1]. Cardinal motor symptoms are most commonly associated with PD, ∼80% of patients report sleep problems such as sleep fragmentation, excessive daytime sleepiness, and rapideye-movement (REM) sleep behavior disorder (RBD) [7]. These symptoms can precede motor symptoms in idiopathic PD by as much as 7 years [8,9,10]. Given that sleep disturbances are a feature of LRRK2 PD [11], there is a need to characterized and identify early sleep alterations unique to LRRK2 PD, as they relate to non-REM (NREM) sleep
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