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

• Published in: Journal of Parkinson's disease Vol. 11; no. 4; pp. 1773 - 1790
• Main Authors: Dos Santos, Altair B., Skaanning, Line K., Mikkelsen, Eyd, Romero-Leguizamón, Cesar R., Kristensen, Morten P., Klein, Anders B., Thaneshwaran, Siganya, Langkilde, Annette E., Kohlmeier, Kristi A.
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.01.2021; IOS Press BV
• Subjects: alpha-Synuclein - metabolism; Calcium (intracellular); Calcium imaging; Calcium signalling; Cell death; Circular dichroism; Electrophysiology; Excitotoxicity; Humans; Movement disorders; Neurodegenerative diseases; Neurons; Neurotoxicity; Parkinson Disease - complications; Parkinson Disease - pathology; Parkinson's disease; Pedunculopontine Tegmental Nucleus - metabolism; Sleep; Sleep disorders; Sleep Wake Disorders - etiology; Spectroscopy; Substantia nigra; Substantia Nigra - metabolism; Synuclein; Tegmentum; Tegmentum Mesencephali - metabolism; neurodegenerative diseases; mechanism of disease; Biomarkers; excessive daytime sleepiness; prodromal phase; neuronal alterations; REM sleep behavior disorder
• ISSN: 1877-7171; 1877-718X
• DOI: 10.3233/JPD-212554

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 fluorescence assays, 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 neurons, 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.