Sleep-controlling neurons are sensitive and vulnerable to multiple forms of α-synuclein: implications for the early appearance of sleeping disorders in α-synucleinopathies
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Sleep-controlling neurons are sensitive and vulnerable to multiple forms of α-synuclein : implications for the early appearance of sleeping disorders in α-synucleinopathies. / 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.
In: Cellular and Molecular Life Sciences, Vol. 79, No. 8, 450, 2022.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
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 - Dos Santos, Altair B
AU - Skaanning, Line K
AU - Thaneshwaran, Siganya
AU - Mikkelsen, Eyd
AU - Romero-Leguizamón, Cesar R
AU - Skamris, Thomas
AU - Kristensen, Morten P
AU - Langkilde, Annette E
AU - Kohlmeier, Kristi A
N1 - © 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.
PY - 2022
Y1 - 2022
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 this 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 this structure-independent manner. These regions may represent highly important targets for future neuroprotective therapy to modify or delay disease progression in α-synucleinopathies.
KW - Calcium
KW - Humans
KW - Neurons/metabolism
KW - Sleep
KW - Synucleinopathies
KW - alpha-Synuclein/metabolism
U2 - 10.1007/s00018-022-04467-z
DO - 10.1007/s00018-022-04467-z
M3 - Journal article
C2 - 35882665
VL - 79
JO - Cellular and Molecular Life Sciences
JF - Cellular and Molecular Life Sciences
SN - 1420-682X
IS - 8
M1 - 450
ER -
ID: 315700347