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
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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. / Brito dos Santos, Altair; Skaanning, Line Koch; Mikkelsen, Eyd ; Leguizamon, Cesar Ramon Romero; Kristensen, Morten Pilgaard; Klein, Anders Bue; Thaneshwaran, Siganya Siganya ; Langkilde, Annette Eva; Kohlmeier, Kristi Anne.
In: Journal of Parkinson's Disease, Vol. 11, No. 4, 2021, p. 1773-1790.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - α-Synuclein Responses in the Laterodorsal Tegmentum, the Pedunculopontine Tegmentum and the Substantia Nigra
T2 - Implications for Early Appearance of Sleep Disorders in Parkinson’s Disease
AU - Brito dos Santos, Altair
AU - Skaanning, Line Koch
AU - Mikkelsen, Eyd
AU - Leguizamon, Cesar Ramon Romero
AU - Kristensen, Morten Pilgaard
AU - Klein, Anders Bue
AU - Thaneshwaran, Siganya Siganya
AU - Langkilde, Annette Eva
AU - Kohlmeier, Kristi Anne
PY - 2021
Y1 - 2021
N2 - Background:Parkinson’s disease (PD) is a neurodegenerative disorder associated with insoluble pathological aggregates of the protein α-synuclein. While PD is diagnosed by motor symptoms putatively due to aggregated α-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 α-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 α-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 emission, and circular dichroism spectroscopy were used to isolate structurally defined forms of recombinant, human α-synuclein. Neuronal and viability effects of characterized monomeric and fibril forms of α-synuclein were determined on LDT, PPT, and SN neurons using electrophysiology, calcium imaging, and neurotoxicity assays. Results:In LDT and PPT, both forms of α-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 α-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 α-synuclein compromises functionality of sleep-control neurons, leading to the presence of SDs decades prior to motor dysfunction.
AB - Background:Parkinson’s disease (PD) is a neurodegenerative disorder associated with insoluble pathological aggregates of the protein α-synuclein. While PD is diagnosed by motor symptoms putatively due to aggregated α-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 α-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 α-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 emission, and circular dichroism spectroscopy were used to isolate structurally defined forms of recombinant, human α-synuclein. Neuronal and viability effects of characterized monomeric and fibril forms of α-synuclein were determined on LDT, PPT, and SN neurons using electrophysiology, calcium imaging, and neurotoxicity assays. Results:In LDT and PPT, both forms of α-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 α-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 α-synuclein compromises functionality of sleep-control neurons, leading to the presence of SDs decades prior to motor dysfunction.
U2 - 10.3233/JPD-212554
DO - 10.3233/JPD-212554
M3 - Journal article
C2 - 34151857
VL - 11
SP - 1773
EP - 1790
JO - Journal of Parkinson's Disease
JF - Journal of Parkinson's Disease
SN - 1877-7171
IS - 4
ER -
ID: 262997496