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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

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Abstract

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.

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Abbreviations

α-syn:

α-Synuclein

LDT:

Laterodorsal tegmental nucleus

PPT:

Pedunculopontine tegmental nucleus

PD:

Parkinson’s disease

SDs:

Sleeping disorders

REM:

Rapid eye movement

ThT:

Thioflavin T fluorescence spectroscopy

CD:

Circular dichroism spectroscopy

TEM:

Transmission electron microscope

SEC:

Size exclusion chromatography

GPCR:

G-protein coupled receptor

bNOS:

Brain derived nitric oxide synthase

sEPSCs:

Spontaneous excitatory post synaptic currents

α-synF :

Fibril form of α-synuclein

α-synO :

Oligomeric form of α-synuclein

α-synM :

Monomeric form of α-synuclein

Hz:

Hertz

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Funding

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Brazil for funding support in the form of a Ph.D Grant to Altair Brito dos Santos. LKS, TS and AEL acknowledge funding from the Lundbeck Foundation Initiative BRAINSTRUC (2015-2666).

Author information

Authors and Affiliations

  1. Department of Drug Design and PharmacologyFaculty of Health and Medical Sciences, University of Copenhagen, 2100, Copenhagen, Denmark

    Altair B. Dos Santos, Line K. Skaanning, Siganya Thaneshwaran, Eyd Mikkelsen, Cesar R. Romero-Leguizamón, Thomas Skamris, Annette E. Langkilde & Kristi A. Kohlmeier

  2. Department of Neuroscience, University of Copenhagen, 2200, Copenhagen, Denmark

    Altair B. Dos Santos

  3. Academic Services, 3500, Værløse, Denmark

    Morten P. Kristensen

Authors
  1. Altair B. Dos Santos
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  2. Line K. Skaanning
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  3. Siganya Thaneshwaran
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  4. Eyd Mikkelsen
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  5. Cesar R. Romero-Leguizamón
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  6. Thomas Skamris
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  7. Morten P. Kristensen
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  8. Annette E. Langkilde
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  9. Kristi A. Kohlmeier
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Contributions

ABDS, MPK and KAK initiated the study and designed the experimental strategy. LKS, TSP, and AEL expressed and characterized protein structure. ABDS, ST and EM performed and analyzed electrophysiological, and calcium imaging experiments. ABDS and CRRL performed neurodegeneration imaging experiments and data analyzes. ABDS and KAK performed statistical evaluations. LKS, AEL, EM, ST, MPK, ABDS and KAK prepared figures. ABDS, AEL, MPK and KAK wrote the paper, and all authors provided critical feedback on early drafts. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Kristi A. Kohlmeier.

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Conflict of interest

All authors declare that there are no conflicts of interest in regard to this manuscript.

data availability

upon acceptance, data are available at a repository at the university of copenhagen and made available upon reasonable request to the authors.

ethics approval

Animals were used under approval in accordance with European Communities Council Directive (86/609/EEC).

Statement about data used in another study

In the data set reporting amplitudes of effects with monomer and fibril, some of the same data were used in a previously published study (2021;11(4):1773–1790. https://doi.org/10.3233/JPD-212554). However, the present report represents a distinctly different study as it examines a hypothesis, and presents conclusions which are different from those in the earlier publication. In addition, we present the results of many new experiments in this report.

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Dos Santos, A.B., Skaanning, L.K., Thaneshwaran, S. et al. Sleep-controlling neurons are sensitive and vulnerable to multiple forms of α-synuclein: implications for the early appearance of sleeping disorders in α-synucleinopathies. Cell. Mol. Life Sci. 79, 450 (2022). https://doi.org/10.1007/s00018-022-04467-z

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  • DOI: https://doi.org/10.1007/s00018-022-04467-z

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