From Synaptic Physiology to Synaptic Pathology: The Enigma of α-Synuclein

Nordengen, Kaja; Morland, Cecilie

doi:10.3390/ijms25020986

Cited by 8 publications

(4 citation statements)

References 162 publications

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“…Together, these and other APO-produced differences in KO and WT mice pointed to an enhanced sensitivity of DA receptors in KO mice. A peculiar role of each of the synucleins or their combinations in the revealed super-sensitivity of the DA receptors seems to be determined by their involvement in various stages of DA metabolism and its release, reuptake, and recycling [21,34,35]. Betasyn has been shown to potentiate synaptic vesicle DA uptake, but in the absence of other synucleins [6], this seems to explain an extremely low level of EEG coherence suppression in A-B+G-mice (Figure 4B) in contrast to intensive expression of this phenomenon in other KO mice.…”

Section: Discussionmentioning

confidence: 99%

Disruption of Electroencephalogram Coherence between Cortex/Striatum and Midbrain Dopaminergic Regions in the Knock-Out Mice with Combined Loss of Alpha, Beta, and Gamma Synucleins

Vorobyov,

Deev,

Chaprov

et al. 2024

Biomedicines

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The malfunctioning of the brain synucleins is associated with pathogenesis of Parkinson’s disease. Synucleins’ ability to modulate various pre-synaptic processes suggests their modifying effects on the electroencephalogram (EEG) recorded from different brain structures. Disturbances in interrelations between them are critical for the onset and evolution of neurodegenerative diseases. Recently, we have shown that, in mice lacking several synucleins, differences between the frequency spectra of EEG from different brain structures are correlated with specificity of synucleins’ combinations. Given that EEG spectra are indirect characteristics of inter-structural relations, in this study, we analyzed a coherence of instantaneous values for EEGs recorded from different structures as a direct measure of “functional connectivity” between them. Methods: EEG data from seven groups of knock-out (KO) mice with combined deletions of alpha, beta, and gamma synucleins versus a group of wild-type (WT) mice were compared. EEG coherence was estimated between the cortex (MC), putamen (Pt), ventral tegmental area (VTA), and substantia nigra (SN) in all combinations. Results: EEG coherence suppression, predominantly in the beta frequency band, was observed in KO mice versus WT littermates. The suppression was minimal in MC-Pt and VTA-SN interrelations in all KO groups and in all inter-structural relations in mice lacking either all synucleins or only beta synuclein. In other combinations of deleted synucleins, significant EEG coherence suppression in KO mice was dominant in relations with VTA and SN. Conclusion: Deletions of the synucleins produced significant attenuation of intra-cerebral EEG coherence depending on the imbalance of different types of synucleins.

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Section: Discussionmentioning

confidence: 99%

Disruption of Electroencephalogram Coherence between Cortex/Striatum and Midbrain Dopaminergic Regions in the Knock-Out Mice with Combined Loss of Alpha, Beta, and Gamma Synucleins

Vorobyov,

Deev,

Chaprov

et al. 2024

Biomedicines

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“…As mentioned above, α-synuclein, misfolded and accumulated in Levy bodies, is implicated in the pathogenesis of synucleinopathies and is considered a hallmark of PD [126].…”

Section: Trp-kyn Pathway In Pdmentioning

confidence: 97%

“…As mentioned above, α-synuclein, misfolded and accumulated in Levy bodies, is implicated in the pathogenesis of synucleinopathies and is considered a hallmark of PD [ 126 ]. Aberrant soluble oligomers may disrupt cellular homeostasis and induce neuronal death through various intracellular targets.…”

Section: Tryptophan Metabolismmentioning

confidence: 99%

Microbiota, Tryptophan and Aryl Hydrocarbon Receptors as the Target Triad in Parkinson’s Disease—A Narrative Review

Iwaniak,

Owe-Larsson,

Urbańska

2024

IJMS

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In the era of a steadily increasing lifespan, neurodegenerative diseases among the elderly present a significant therapeutic and socio-economic challenge. A properly balanced diet and microbiome diversity have been receiving increasing attention as targets for therapeutic interventions in neurodegeneration. Microbiota may affect cognitive function, neuronal survival and death, and gut dysbiosis was identified in Parkinson’s disease (PD). Tryptophan (Trp), an essential amino acid, is degraded by microbiota and hosts numerous compounds with immune- and neuromodulating properties. This broad narrative review presents data supporting the concept that microbiota, the Trp-kynurenine (KYN) pathway and aryl hydrocarbon receptors (AhRs) form a triad involved in PD. A disturbed gut–brain axis allows the bidirectional spread of pro-inflammatory molecules and α-synuclein, which may contribute to the development/progression of the disease. We suggest that the peripheral levels of kynurenines and AhR ligands are strongly linked to the Trp metabolism in the gut and should be studied together with the composition of the microbiota. Such an approach can clearly delineate the sub-populations of PD patients manifesting with a disturbed microbiota–Trp-KYN–brain triad, who would benefit from modifications in the Trp metabolism. Analyses of the microbiome, Trp-KYN pathway metabolites and AhR signaling may shed light on the mechanisms of intestinal distress and identify new targets for the diagnosis and treatment in early-stage PD. Therapeutic interventions based on the combination of a well-defined food regimen, Trp and probiotics seem of potential benefit and require further experimental and clinical research.

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“…LBDs are a group of progressive neurodegenerative diseases, classed as alpha-synucleinopathies, that are caused by the abnormal accumulation of the pre-synaptic protein alpha-synuclein (α-syn) into toxic oligomers and fibrils that form the Lewy bodies (Spillantini et al, 1998 ). These toxic forms of clustered α-syn then lead to synaptic dysfunction, network oscillation abnormalities, and ultimately cell death (Saramowicz et al, 2023 ; Nordengen and Morland, 2024 ). Chronic neuroinflammation is evident in PD brains where microglia activation is seen in areas with high levels of α-syn aggregates (Iba et al, 2020 , 2023 ).…”

Section: Introductionmentioning

confidence: 99%

Evidence for prodromal changes in neuronal excitability and neuroinflammation in the hippocampus in young alpha-synuclein (A30P) transgenic mice

Al-Musawi,

Dennis,

Clowry

et al. 2024

Front. Dement.

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IntroductionNeuronal hyperexcitability and neuroinflammation are thought to occur at early stages in a range of neurodegenerative diseases. Neuroinflammation, notably activation of microglia, has been identified as a potential prodromal marker of dementia with Lewy bodies (DLB). Using a transgenic mouse model of DLB that over-expresses human mutant (A30P) alpha-synuclein (hα-syn) we have investigated whether early neuroinflammation is evident in the hippocampus in young pre-symptomatic animals.MethodsPrevious studies have shown early hyperexcitability in the hippocampal CA3 region in male A30P mice at 2–4 months of age, therefore, in the current study we have immunostained this region for markers of neuronal activity (c-Fos), reactive astrocytes (glial fibrillary acidic protein, GFAP), microglia (ionizing calcium binding adapter protein 1, Iba-1) and reactive microglia (inducible nitric oxide synthase, iNOS).ResultsWe found an interesting biphasic change in the expression of c-Fos in A30P mice with high expression at 1 month, consistent with early onset of hyperexcitability, but lower expression from 2–4 months in male A30P mice compared to wild-type (WT) controls, possibly indicating chronic hyperexcitability. Neuroinflammation was indicated by significant increases in the % area of GFAP and the number of Iba-1+ cells that expressed iNOS immunoreactivity in the CA3 region in 2–4 months A30P male mice compared to WT controls. A similar increase in % area of GFAP was observed in female A30P mice, however, the Iba-1 count was not different between female WT and A30P mice. In WT mice aged 2–4 months only 4.6% of Iba-1+ cells co-expressed iNOS. In contrast, in age matched A30P mice 87% of cells co-expressed Iba-1 and iNOS. Although there was no difference in GFAP immunoreactivity at 1 month, Iba-1/iNOS co-expression was also increased in a cohort of 1 month old A30P mice.DiscussionAbnormal hα-syn expression in A30P mice caused early changes in network excitability, as indicated by c-Fos expression, and neuroinflammation which might contribute to disease progression.

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From Synaptic Physiology to Synaptic Pathology: The Enigma of α-Synuclein

Cited by 8 publications

References 162 publications

Disruption of Electroencephalogram Coherence between Cortex/Striatum and Midbrain Dopaminergic Regions in the Knock-Out Mice with Combined Loss of Alpha, Beta, and Gamma Synucleins

Disruption of Electroencephalogram Coherence between Cortex/Striatum and Midbrain Dopaminergic Regions in the Knock-Out Mice with Combined Loss of Alpha, Beta, and Gamma Synucleins

Microbiota, Tryptophan and Aryl Hydrocarbon Receptors as the Target Triad in Parkinson’s Disease—A Narrative Review

Evidence for prodromal changes in neuronal excitability and neuroinflammation in the hippocampus in young alpha-synuclein (A30P) transgenic mice

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