Category: Parkinson's Disease: Pathophysiology
To recapitulate ɑ-synucleinopathy based RBD-like behaviors in mice which could further proceed to develop Parkinsonian behavioral and histopathological phenotypes.
Idiopathic REM sleep behavior disorder (RBD), characterized by skeletal muscle atonia loss and dream-enactment behaviors during REM sleep, is proven to be a prodromal biomarker of ɑ-synucleinopathies such as Parkinson’s disease (PD), multiple system atrophy (MSA) and dementia with Lewy body (DLB) . Accumulating clinical and experimental evidence suggests that degeneration or incapacitation of the sublaterodorsal tegmental nucleus (SLD) can lead to RBD phenotypes in human and animals [2-5]. Nevertheless, despite the fact that manipulative incapacitation of the SLD nucleus induces typical RBD-like behaviors in animals, it cannot reflect the synucleinopathy essence of idiopathic RBD and fails to mimic the conversion process of RBD to PD [6, 7].
Method: The study methods were divided into three parts: Part I~III. Firstly, in Part I, we established the preparation protocol of preformed a-syn fibrils (PFFs) and characterized the morphology and beta-sheet structure of PFFs. Then, in Part II, we injected PFFs into mouse SLD nucleus and performed video-polysomnography (PSG) recordings. After the PSG recording, we sacrificed the mice and determined the neuron survival status and a-syn pathology in SLD. At last, in Part III, we performed a battery of Parkinsonian behavioral tests and histopathological studies on the mice that receiving PFFs injection.
In this study, we demonstrated that the mice receiving PFFs injection displayed typical RBD-like behaviors, accompanying progressive neuron entity loss and pathological ɑ-synuclein aggregation in the SLD. Moreover, the RBD mice gradually proceeded to exhibit Parkinsonian motor & non-motor deficits, concomitant with worsening nigrostriatal degeneration and spreading ɑ-synuclein pathology across the whole brain. Apart from these, we also revealed typical Lewy pathology in the subcoeruleus nucleus of an RBD/PD patient, which provided human tissue-based neuropathological evidence for animal study findings of this study.
In conclusion, we introduced a synucleinopathy-based RBD modeling strategy, which could not only help to explore the neuropathogenic mechanism of RBD but also be used to develop disease-modifying therapeutics for PD.
References: 1. Högl B, Stefani A, Videnovic A. Idiopathic REM sleep behaviour disorder and neurodegeneration—an update[J]. Nature Reviews Neurology, 2018, 14(1): 40. 2. García-Lorenzo D, Longo-Dos Santos C, Ewenczyk C, et al. The coeruleus/subcoeruleus complex in rapid eye movement sleep behaviour disorders in Parkinson’s disease. Brain, 2013, 136(7): 2120-2129. 3. Valencia Garcia S, Libourel P A, Lazarus M, et al. Genetic inactivation of glutamate neurons in the rat sublaterodorsal tegmental nucleus recapitulates REM sleep behaviour disorder[J]. Brain, 2017, 140(2): 414-428. 4. Lu J, Sherman D, Devor M, et al. A putative flip–flop switch for control of REM sleep[J]. Nature, 2006, 441(7093): 589-594. 5. Krenzer M, Anaclet C, Vetrivelan R, et al. Brainstem and spinal cord circuitry regulating REM sleep and muscle atonia[J]. PloS one, 2011, 6(10): e24998. 6. Peever J, Luppi P H, Montplaisir J. Breakdown in REM sleep circuitry underlies REM sleep behavior disorder[J]. Trends in neurosciences, 2014, 37(5): 279-288. 7. McKenna D, Peever J. Degeneration of rapid eye movement sleep circuitry underlies rapid eye movement sleep behavior disorder[J]. Movement Disorders, 2017, 32(5): 636-644.
To cite this abstract in AMA style:Y. Shen, W.B Yu, B. Shen, H. Dong, J. Zhao, Y. Fan, Y.F Yang, Y.M Sun, Y.L Tang, F.T Liu, JJ. Wu, B.G Xiao, H. Yu, J. Koprich, Z.L Huang, J. Wang. Spreading ɑ-synuclein pathology initiated from the sublaterodorsal tegmental nucleus models RBD followed by Parkinsonian phenotypes in mice [abstract]. Mov Disord. 2020; 35 (suppl 1). https://www.mdsabstracts.org/abstract/spreading-a-synuclein-pathology-initiated-from-the-sublaterodorsal-tegmental-nucleus-models-rbd-followed-by-parkinsonian-phenotypes-in-mice/. Accessed November 29, 2023.
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