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Morawska MM, Moreira CG, Ginde VR, Valko PO, Weiss T, Büchele F, Imbach LL, Masneuf S, Kollarik S, Prymaczok N, Gerez JA, Riek R, Baumann CR, Noain D. Slow-wave sleep affects synucleinopathy and regulates proteostatic processes in mouse models of Parkinson's disease. Sci Transl Med. 2021 Dec 8;13(623):eabe7099. PubMed.
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Washington University School of Medicine
Morawska et al. have expanded upon previous studies showing that sleep enhancement/deprivation can influence Aβ and tau deposition to now show that the same holds true for α-synuclein. They have taken care to characterize the effects of sodium oxybate on slow-wave sleep in mice, and use this intervention to enhance SWS in two different models of α-synucleinopathy, both of which are major strengths.
They also added a sleep-deprivation arm using the platform-over-water method. In general, sleep deprivation increases synuclein aggregation, while SWS enhancement mitigates it. It is difficult to compare the sleep-deprivation and -enhancement methods directly, as one is pharmacological (oxybate) and the other behavioral, and potentially stressful. However, this relationship is similar to that seen with other pathogenic proteins.
Mechanistically, there are some interesting leads but no very specific conclusions at this point. There is some change in Aqp4 staining, though the effect seemed quite modest and not really enough in my opinion to conclude anything about glymphatic function. Proteomics revealed a signature of increased lysosomal function, ubiquitin function, protein folding/breakdown with sleep enhancement and a reciprocal effect in deprivation. These findings are consistent with other studies, suggesting that sleep regulates proteostasis broadly.
The findings also dovetail nicely with previous work from Brendan Lucey, David Holtzman, and colleagues showing increased CSF α-synuclein in humans after sleep deprivation (see Holth et al., 2019). Morawska et al. have presented an important observation for the Parkinson's disease field, as well as for dementia with Lewy bodies research. This should open the door for further study of sleep in these conditions and possible therapeutic use of sleep-modifying agents.
References:
Holth JK, Fritschi SK, Wang C, Pedersen NP, Cirrito JR, Mahan TE, Finn MB, Manis M, Geerling JC, Fuller PM, Lucey BP, Holtzman DM. The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans. Science. 2019 Feb 22;363(6429):880-884. Epub 2019 Jan 24 PubMed.
View all comments by Erik MusiekUniversity of Toronto
This is a really exciting paper. It provides evidence that, in at least some model systems for synucleinopathy, sleep manipulations can in principle affect the accumulation of synuclein neuropathology. As such, it does for synucleinopathies what previous papers by Kang and colleagues (Kang et al., 2009) and Holth and colleagues (Holth et al., 2019) did for amyloid and tau, respectively.
From a mechanistic perspective, I think important questions remain, including to what degree these effects are driven by neuronal activity/production versus extracellular clearance versus modulation of proteostatic mechanisms.
From a translational perspective, the extent to which these mechanisms are important in human synucleinopathies like Parkinson’s disease remains a completely open question. There will be several challenges in answering this question.
First, we will need appropriate sleep therapeutic interventions in older adults that will have a similar effect on slow-wave sleep as sodium oxybate, without the safety issues that surround use of this drug in older patients with and without PD. It is likely that for any intervention to be effective in patients, it will need to be given long-term, and possibly to neurologically asymptomatic patients, and it is not clear that sodium oxybate fits the bill given its propensity to cause adverse effects in older adults.
Second, we lack great biomarker readouts for the burden of synuclein pathology in humans. While all this work is being done, I do think this study provides a mechanistic rationale for using existing tools to optimize sleep in patients with, or at risk for, synucleinopathies. While we cannot yet say that this will for sure slow progression of synuclein pathology, there is at least now a rationale for believing that it might.
References:
Kang JE, Lim MM, Bateman RJ, Lee JJ, Smyth LP, Cirrito JR, Fujiki N, Nishino S, Holtzman DM. Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. Science. 2009 Nov 13;326(5955):1005-7. PubMed.
Holth JK, Fritschi SK, Wang C, Pedersen NP, Cirrito JR, Mahan TE, Finn MB, Manis M, Geerling JC, Fuller PM, Lucey BP, Holtzman DM. The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans. Science. 2019 Feb 22;363(6429):880-884. Epub 2019 Jan 24 PubMed.
View all comments by Andrew LimUniversity Hospital Zurich
The main finding of this compelling study is that modulating sleep slow waves influences neuropathological outcome in two different mouse models of α-synucleinopathy. Specifically, the study showed less α-synuclein accumulation after enhancing slow waves with sodium oxybate compared to placebo, whereas sleep deprivation had an opposite effect. Intriguingly, the authors identified changes in the AQP4-mediated/glymphatic pathway and several processes related to protein homeostasis as potential mechanisms through which sleep slow waves could influence accumulation of α-synuclein.
These findings fit with previous studies on the link between slow-wave sleep and pathological protein accumulation in Alzheimer's disease and imply that similar mechanisms could be present in synucleinopathies such as Parkinson's disease.
As such, the findings resonate with our clinical studies in people with Parkinson's, suggesting that deeper slow-wave sleep is associated with better cognitive performance cross-sectionally and slower motor progression over time, although prospective confirmation of the latter observation is pending.
The present study is exciting, as it provides more rationale to further explore the role and therapeutic potential of sleep, especially slow-wave sleep, in clinical populations with neurodegenerative disorders, including synucleinopathies. This is of interest because there are pharmacological and emerging, highly specific non-pharmacological methods for enhancing slow-wave sleep in humans.
There are several additional findings, including (1) sex differences in the therapeutic response, (2) important observations on the trajectories of sleep, behavioral impairment, and neuropathology in synuclein mice, and (3) discordance between neuropathological and clinical outcome, which warrant further exploration.
View all comments by Simon J. SchreinerMake a Comment
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