Sleep-controlling neurons are sensitive and vulnerable to multiple forms of α-synuclein: implications for the early appearance of sleeping disorders in α-synucleinopathies

• Published in: Cellular and molecular life sciences : CMLS Vol. 79; no. 8; p. 450
• Main Authors: Dos Santos, Altair B., Skaanning, Line K., Thaneshwaran, Siganya, Mikkelsen, Eyd, Romero-Leguizamón, Cesar R., Skamris, Thomas, Kristensen, Morten P., Langkilde, Annette E., Kohlmeier, Kristi A.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.08.2022; Springer Nature B.V
• Subjects: alpha-Synuclein - metabolism; Atrophy; Biochemistry; Biomedical and Life Sciences; Biomedicine; Brain stem; Calcium; Calcium (intracellular); Calcium imaging; Cell Biology; Cell death; Circular dichroism; Dementia disorders; Dichroism; Disease; Disorders; Electrophysiology; Fluorescence spectroscopy; Humans; Laterodorsal tegmental nucleus; Lewy bodies; Life Sciences; Medical imaging; Membrane currents; Movement disorders; Neurodegenerative diseases; Neuroimaging; Neurons; Neurons - metabolism; Neuroprotection; Neurotransmitters; Nuclei (cytology); Original; Original Article; Parkinson's disease; Pedunculopontine tegmental nucleus; Proteins; Size exclusion chromatography; Sleep; Spectroscopy; Spectrum analysis; Structural forms; Synuclein; Synucleinopathies; Transmission electron microscopy; Sleep disorders; Neurodegenerative disease; α-synucleinopathies; Pedunculopontine tegmental nucleus; Laterodorsal tegmental nucleus; α-synuclein
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s00018-022-04467-z

Parkinson’s disease, Multiple System Atrophy, and Lewy Body Dementia are incurable diseases called α-synucleinopathies as they are mechanistically linked to the protein, α-synuclein (α-syn). α-syn exists in different structural forms which have been linked to clinical disease distinctions. However, sleeping disorders (SDs) are common in the prodromal phase of all three α-synucleinopathies, which suggests that sleep-controlling neurons are affected by multiple forms of α-syn. To determine whether a structure-independent neuronal impact of α-syn exists, we compared and contrasted the cellular effect of three different α-syn forms on neurotransmitter-defined cells of two sleep-controlling nuclei located in the brainstem: the laterodorsal tegmental nucleus and the pedunculopontine tegmental nucleus. We utilized size exclusion chromatography, fluorescence spectroscopy, circular dichroism spectroscopy and transmission electron microscopy to precisely characterize ​​timepoints in the α-syn aggregation process with three different dominating forms of this protein (monomeric, oligomeric and fibril) and we conducted an in-depth investigation of the underlying neuronal mechanism behind cellular effects of the different forms of the protein using electrophysiology, multiple-cell calcium imaging, single-cell calcium imaging and live-location tracking with fluorescently-tagged α-syn. Interestingly, α-syn altered membrane currents, enhanced firing, increased intracellular calcium and facilitated cell death in a structure-independent manner in sleep-controlling nuclei, and postsynaptic actions involved a G-protein-mediated mechanism. These data are novel as the sleep-controlling nuclei are the first brain regions reported to be affected by α-syn in this structure-independent manner. These regions may represent highly important targets for future neuroprotective therapy to modify or delay disease progression in α-synucleinopathies.