Sleep Dysfunction and EEG Alterations in Mice Overexpressing Alpha-Synuclein

McDowell, Kimberly A.; Shin, Dongsuk; Roos, Kenneth P.; Chesselet, Marie‐Françoise

doi:10.3233/jpd-140374

Cited by 52 publications

(47 citation statements)

References 32 publications

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“…We used mice overexpressing human, WT α-synuclein under the murine Thy-1 promoter (Thy1-aSyn) [31], which has been characterized thoroughly in the Chesselet laboratory. This mouse model reproduces multiple features of PD including motor dysfunction, nonmotor deficits, mitochondrial dysfunction, inflammation, α-synuclein pathology, and dopamine loss [15,[32][33][34][35][36][37][38][39]. Our data show that amelioration of motor deficits following treatment with CLR01 associates with clearance of buffer-soluble α-synuclein but not insoluble α-synuclein aggregates.…”

Section: Introductionmentioning

confidence: 59%

A Molecular Tweezer Ameliorates Motor Deficits in Mice Overexpressing α-Synuclein

et al. 2017

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Aberrant accumulation and self-assembly of α-synuclein are tightly linked to several neurodegenerative diseases called synucleinopathies, including idiopathic Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Deposition of fibrillar α-synuclein as insoluble inclusions in affected brain cells is a pathological hallmark of synucleinopathies. However, water-soluble α-synuclein oligomers may be the actual culprits causing neuronal dysfunction and degeneration in synucleinopathies. Accordingly, therapeutic approaches targeting the toxic α-synuclein assemblies are attractive for these incurable disorders. The "molecular tweezer" CLR01 selectively remodels abnormal protein self-assembly through reversible binding to Lys residues. Here, we treated young male mice overexpressing human wild-type α-synuclein under control of the Thy-1 promoter (Thy1-aSyn mice) with CLR01 and examined motor behavior and α-synuclein in the brain. Intracerebroventricular administration of CLR01 for 28 days to the mice improved motor dysfunction in the challenging beam test and caused a significant decrease of buffer-soluble α-synuclein in the striatum. Proteinase-K-resistant, insoluble α-synuclein deposits remained unchanged in the substantia nigra, whereas levels of diffuse cytoplasmic α-synuclein in dopaminergic neurons increased in mice receiving CLR01 compared with vehicle. More moderate improvement of motor deficits was also achieved by subcutaneous administration of CLR01, in 2/5 trials of the challenging beam test and in the pole test, which requires balance and coordination. The data support further development of molecular tweezers as therapeutic agents for synucleinopathies.

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Section: Introductionmentioning

confidence: 59%

A Molecular Tweezer Ameliorates Motor Deficits in Mice Overexpressing α-Synuclein

et al. 2017

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“…The olfactory nucleus may also be involved at the time of medullary Lewy body pathology, although neurodegeneration begins in the substantia nigra. Wild-type α-synuclein overexpression leading to brain stem and cortical accumulation is associated with sleep disturbances in mice 171 . The concept of early brain stem involvement has been used to explain the early non-motor features of hyposmia and sleep disturbance in patients with PD 172,173 .…”

Section: [H1] Neuropsychiatric Featuresmentioning

confidence: 99%

Non-motor features of Parkinson disease

2017

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Many of the motor symptoms of Parkinson disease (PD) can be preceded, sometimes for several years, by non-motor symptoms that include hyposmia, sleep disorders, depression and constipation. These non-motor features appear across the spectrum of patients with PD, including individuals with genetic causes of PD. The neuroanatomical and neuropharmacological bases of non-motor abnormalities in PD remain largely undefined. Here, we discuss recent advances that have helped to establish the presence, severity and effect on the quality of life of non-motor symptoms in PD, and the neuroanatomical and neuropharmacological mechanisms involved. We also discuss the potential for the non-motor features to define a prodrome that may enable the early diagnosis of PD.

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“…SNCA encodes α -synuclein and has been implicated in rapid eye movement (REM) sleep behavior disorder 34 and Parkinson's disease 35 . Altered expression in mice changes sleep and wake electroencephalogram spectra 36 along the same dimensions that have been implicated in insomnia disorder 37 . DNM1 encodes the synaptic neuronal protein dynamin 1, which is increased in BTBD9 mutant mice 30 and mediates the sleep-disruptive effect of presleep arousal (see earlier; BTBD9 is the top associated gene).…”

Section: Implicated Pathways Tissues and Cell Typesmentioning

confidence: 98%