Slow-wave sleep affects synucleinopathy and regulates proteostatic processes in mouse models of Parkinson's disease

被引:47
作者
Morawska, Marta M. [1 ,2 ]
Moreira, Carlos G. [1 ,3 ]
Ginde, Varun R. [1 ]
Valko, Philipp O. [1 ]
Weiss, Tobias [1 ]
Buechele, Fabian [1 ]
Imbach, Lukas L. [1 ]
Masneuf, Sophie [1 ]
Kollarik, Sedef [1 ,2 ]
Prymaczok, Natalia [4 ]
Gerez, Juan A. [4 ]
Riek, Roland [4 ]
Baumann, Christian R. [1 ,2 ,5 ]
Noain, Daniela [1 ,2 ,5 ]
机构
[1] Univ Hosp Zurich USZ, Dept Neurol, Frauenklin Str 26, CH-8091 Zurich, Switzerland
[2] Univ Zurich UZH, Neurosci Ctr Zurich ZNZ, Winterthurerstr 190, CH-8057 Zurich, Switzerland
[3] Swiss Fed Inst Technol, Neurosci Ctr Zurich ZNZ, Winterthurerstr 190, CH-8057 Zurich, Switzerland
[4] Swiss Fed Inst Technol, Lab Phys Chem, Dept Chem & Appl Biosci, Vladimir Prelog Weg 2, CH-8093 Zurich, Switzerland
[5] Univ Zurich, Ctr Competence Sleep & Hlth Zurich, Frauenklin Str 26, CH-8091 Zurich, Switzerland
基金
瑞士国家科学基金会;
关键词
UBIQUITIN-PROTEASOME SYSTEM; ALPHA-SYNUCLEIN; PROTEIN-DEGRADATION; DAYTIME SLEEPINESS; BEHAVIOR DISORDER; SODIUM OXYBATE; BRAIN; EEG; MICE; NEURODEGENERATION;
D O I
10.1126/scitranslmed.abe7099
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Slow-wave sleep (SWS) modulation in rodent models of Alzheimer's disease alters extracellular amyloid burden. In Parkinson's disease (PD), SWS appears to be closely linked with disease symptoms and progression. PD is characterized by damaging intracellular alpha-synuclein (alpha Syn) deposition that propagates extracellularly, contributing to disease spread. Intracellular alpha Syn is sensitive to degradation, whereas extracellular alpha Syn may be eliminated by glymphatic clearance, a process increased during SWS. Here, we explored whether long-term slow-wave modulation in murine models of PD presenting alpha Syn aggregation alters pathological protein burden and, thus, might constitute a valuable therapeutic target. Sleep-modulating treatments showed that enhancing slow waves in both VMAT2-deficient and A53T mouse models of PD reduced pathological alpha Syn accumulation compared to control animals. Nonpharmacological sleep deprivation had the opposite effect in VMAT2-deficient mice, severely increasing the pathological burden. We also found that SWS enhancement was associated with increased recruitment of aquaporin-4 to perivascular sites, suggesting a possible increase of glymphatic function. Furthermore, mass spectrometry data revealed differential and specific up-regulation of functional protein clusters linked to proteostasis upon slow wave-enhancing interventions. Overall, the beneficial effect of SWS enhancement on neuropathological outcome in murine synucleinopathy models mirrors findings in models of Alzheimer. Modulating SWS might constitute an effective strategy for modulating PD pathology in patients.
引用
收藏
页数:13
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