α-Synuclein Responses in the Laterodorsal Tegmentum, the Pedunculopontine Tegmentum and the Substantia Nigra: Implications for Early Appearance of Sleep Disorders in Parkinson’s Disease
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Background:Parkinson’s disease (PD) is a neurodegenerative disorder associated with insoluble pathological aggregates of the protein α-synuclein. While PD is diagnosed by motor symptoms putatively due to aggregated α-synuclein-mediated damage to substantia nigra (SN) neurons, up to a decade before motor symptom appearance, patients exhibit sleep disorders (SDs). Therefore, we hypothesized that α-synuclein, which can be present in monomeric, fibril, and other forms, has deleterious cellular actions on sleep-control nuclei. Objective:We investigated whether native monomer and fibril forms of α-synuclein have effects on neuronal function, calcium dynamics, and cell-death-induction in two sleep-controlling nuclei: the laterodorsal tegmentum (LDT), and the pedunculopontine tegmentum (PPT), as well as the motor-controlling SN. Methods:Size exclusion chromatography, Thioflavin T emission, and circular dichroism spectroscopy were used to isolate structurally defined forms of recombinant, human α-synuclein. Neuronal and viability effects of characterized monomeric and fibril forms of α-synuclein were determined on LDT, PPT, and SN neurons using electrophysiology, calcium imaging, and neurotoxicity assays. Results:In LDT and PPT, both forms of α-synuclein induced excitation and increased calcium, and the monomeric form heightened putatively excitotoxic neuronal death, whereas, in the SN we saw inhibition, decreased intracellular calcium, and monomeric α-synuclein was not associated with heightened cell death. Conclusion:Nucleus-specific differential effects suggest mechanistic underpinnings of SDs’ prodromal appearance in PD. While speculative, we hypothesize that the monomeric form of α-synuclein compromises functionality of sleep-control neurons, leading to the presence of SDs decades prior to motor dysfunction.
Originalsprog | Engelsk |
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Tidsskrift | Journal of Parkinson's Disease |
Vol/bind | 11 |
Udgave nummer | 4 |
Sider (fra-til) | 1773-1790 |
ISSN | 1877-7171 |
DOI | |
Status | Udgivet - 2021 |
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