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

Background: Parkinson's disease (PD) is a neurodegenerative disorder associated with insoluble pathological aggregates of the protein alpha-synuclein. While PD is diagnosed by motor symptoms putatively due to aggregated alpha-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 alpha-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 alpha-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 alpha-synuclein. Neuronal and viability effects of characterized monomeric and fibril forms of alpha-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 alpha-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 alpha-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 alpha-synuclein compromises functionality of sleep-control neurons, leading to the presence of SDs decades prior to motor dysfunction.

Automated summary

In summary, the study found that both monomeric and fibril forms of alpha-synuclein induced excitement and increased calcium in laterodorsal tegmentum and pedunculopontine tegmentum neurons, while the monomeric form heightened neuronal death. In substantia nigra, alpha-synuclein displayed inhibitory effects, decreased intracellular calcium, and monomeric form was not associated with heightened cell death. The nucleus-specific differential effects suggest potential mechanisms underlying sleep disorders' prodromal appearance in Parkinson's disease.