TY - UNPB

T1 - Sleep-controlling neurons are sensitive and vulnerable to multiple forms of α-synuclein

T2 - implications for the early appearance of sleeping disorders in α-synucleinopathies

AU - Santos, Altair B Dos

AU - Skaanning, Line K

AU - Thaneskwaran, Siggania

AU - Mikkelsen, Eyd

AU - Romero-Leguizamon, Cesar R

AU - Skamris, Thomas

AU - Kristensen, Morten P

AU - Langkilde, Annette E

AU - Kohlmeier, Kristi A.

PY - 2022/5/9

Y1 - 2022/5/9

N2 - 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 a structure-independent manner. These regions may represent highly important targets for future neuroprotective therapy to modify or delay disease progression in α-synucleinopathies.

AB - 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 a structure-independent manner. These regions may represent highly important targets for future neuroprotective therapy to modify or delay disease progression in α-synucleinopathies.

U2 - 10.21203/rs.3.rs-1582968/v1

DO - 10.21203/rs.3.rs-1582968/v1

M3 - Preprint

BT - Sleep-controlling neurons are sensitive and vulnerable to multiple forms of α-synuclein

PB - Research Square-Preprint

ER -