Inflammation and α-Synuclein’s Prion-like Behavior in Parkinson's Disease—Is There a Link?

Tomé, Carla M. Lema; Tyson, Trevor; Rey, Nolwen L.; Grathwohl, Stefan; Britschgi, Markus; Brundin, Patrik

doi:10.1007/s12035-012-8267-8

Cited by 199 publications

(158 citation statements)

References 186 publications

(192 reference statements)

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“…More recently, pSer129 >-synuclein was reported in 12-to 14-month-old TgM83 mice and thus not in a complete time-dependent manner (49), as we report here. Furthermore, our results do not provide clear support for the concept that the gastrointestinal tract in PD subjects develops synucleinopathy before the CNS (33,50,51) and rather indicate that there may be a parallel pathologic process in the ENS and the CNS. Further studies are required to test all these possibilities, but the present TgM83 mouse model should prove to be a valuable tool for understanding the role of pSer129 >-synuclein in PD and how peripheral pSer129 >-synuclein expression interferes with progressive neurodegeneration in PD.…”

Section: Discussioncontrasting

confidence: 95%

Early and Persistent Expression of Phosphorylated α-Synuclein in the Enteric Nervous System of A53T Mutant Human α-Synuclein Transgenic Mice

Bencsik

Muselli

Leboidre

et al. 2014

J Neuropathol Exp Neurol

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Alpha-synuclein is a key protein in Parkinson disease (PD) and dementia with Lewy bodies. It is found in Lewy bodies in the brains of PD patients and has been reported in the peripheral nervous system in postmortem tissues from PD patients and in biopsies from patients in the preclinical phase of PD. Here, we used a transgenic mouse model of human synucleinopathies expressing the A53T mutant α-synuclein (TgM83) in which a neurodegenerative process associated with α-synuclein occurs spontaneously and increases with age. In particular, α-synuclein protein phosphorylated at serine 129 (pSer129 α-synuclein) naturally and progressively increases in diseased brains. We examined the time course of pSer129 α-synuclein presence in the gut of these mice between 1.5 and 22 months of age using immunohistochemistry and paraffin-embedded tissue blots. The pSer129 α-synuclein accumulated early (before the onset of motor signs) and persistently in the enteric nervous system and was concomitantly found in the brain. These results suggest that the accumulation of phosphorylated α-synuclein in the enteric and central nervous systems may result from parallel pathologic processes when the disease is linked to a mutation of α-synuclein.

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Section: Discussioncontrasting

confidence: 95%

Early and Persistent Expression of Phosphorylated α-Synuclein in the Enteric Nervous System of A53T Mutant Human α-Synuclein Transgenic Mice

Bencsik

Muselli

Leboidre

et al. 2014

J Neuropathol Exp Neurol

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“…The role of neuron-glia interaction in the etiology of NDDs is an important area of current investigations due to the involvement of naturally unfolded proteins in prion-like transmission of pathology [16-18,24]. The results presented here are in agreement with previous observations of aberrant γ-syn accumulation in the optic nerve astrocytes and spheroids which is not accompanied by the formation of inclusion bodies or deposits [10,11]…”

Section: Discussionsupporting

confidence: 91%

New α- and γ-synuclein immunopathological lesions in human brain

Surgucheva

Newell

Burns

et al. 2014

acta neuropathol commun

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IntroductionSeveral neurodegenerative diseases are classified as proteopathies as they are associated with the aggregation of misfolded proteins. Synucleinopathies are a group of neurodegenerative disorders associated with abnormal deposition of synucleins. α-Synucleinopathies include Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. Recently accumulation of another member of the synuclein family- γ−synuclein in neurodegenerative diseases compelled the introduction of the term γ−synucleinopathy. The formation of aggregates and deposits of γ−synuclein is facilitated after its oxidation at methionine 38 (Met38).ResultsSeveral types of intracytoplasmic inclusions containing post-translationally modified α- and γ−synucleins are detected. Oxidized Met38-γ-synuclein forms aberrant inclusions in amygdala and substantia nigra. Double staining revealed colocalization of oxidized-γ-synuclein with α-synuclein in the cytoplasm of neurons. Another type of synuclein positive inclusions in the amygdala of dementia with Lewy bodies patients has the appearance of Lewy bodies. These inclusions are immunoreactive when analyzed with antibodies to α-synuclein phosphorylated on serine 129, as well as with antibodies to oxidized-γ-synuclein. Some of these Lewy bodies have doughnut-like shape with round or elongated shape. The separate immunofluorescent images obtained with individual antibodies specific to oxidized-γ-synuclein and phospho-α-synuclein clearly shows the colocalization of these synuclein isoforms in substantia nigra inclusions. Phospho-α-synuclein is present almost exclusively at the periphery of these structures, whereas oxidized-γ-syn immunoreactivity is also located in the internal parts forming dot-like pattern of staining.We also identified several types of oxidized-γ-syn positive astrocytes with different morphology and examined their immunohistochemical phenotypes. Some of them are compact cells with short processes, others have longer processes. Oxidized-γ-synuclein positive astrocytes may also display mixed morphological and immunocytochemical phenotypes between protoplasmic and fibrous astrocytes.ConclusionsThese results reveal new γ−synuclein positive lesions in human brain. Oxidized-γ-synuclein is colocalized with phospho-α-synuclein in doughnut-like inclusions. Several types of astrocytes with different morphology are immunopositive for oxidized-γ-synuclein.

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“…Inflammatory cytokines such as IL-1b, TNF-a，INF-g and nitric oxide (NO) derived from microglia and other non-neuronal cells could lead to dopaminergic neuronal degeneration [27e29]. Furthermore, inflammation triggered by bacteria or virus has been proposed to trigger a-synuclein misfolding, aggregation and propagation [30].…”

Section: Discussionmentioning

confidence: 99%

The association between infectious burden and Parkinson's disease: A case-control study

Bu¹,

Wang²,

Xiang³

et al. 2015

Parkinsonism & Related Disorders

135

123

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Inflammation and α-Synuclein’s Prion-like Behavior in Parkinson's Disease—Is There a Link?

Cited by 199 publications

References 186 publications

Early and Persistent Expression of Phosphorylated α-Synuclein in the Enteric Nervous System of A53T Mutant Human α-Synuclein Transgenic Mice

Early and Persistent Expression of Phosphorylated α-Synuclein in the Enteric Nervous System of A53T Mutant Human α-Synuclein Transgenic Mice

New α- and γ-synuclein immunopathological lesions in human brain

The association between infectious burden and Parkinson's disease: A case-control study

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