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

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Parkinson’s disease patients exhibit progressive spreading of aggregated α-synuclein in the nervous system. This slow process follows a specific pattern in an inflamed tissue environment. Recent research suggests that prion-like mechanisms contribute to the propagation of α-synuclein pathology. Little is known about factors that might affect the prion-like behavior of misfolded α-synuclein. In this review, we suggest that neuroinflammation plays an important role. We discuss causes of inflammation in the olfactory bulb and gastrointestinal tract and how this may promote the initial misfolding and aggregation of α-synuclein, which might set in motion events that lead to Parkinson's disease neuropathology. We propose that neuroinflammation promotes the prion-like behavior of α-synuclein and that novel anti-inflammatory therapies targeting this mechanism could slow disease progression.

Related collections

Most cited references 118

Record: found
Abstract: found
Article: not found

alpha-Synuclein is phosphorylated in synucleinopathy lesions.

Hideo Fujiwara, Masato Hasegawa, Naoshi Dohmae … (2002)

The deposition of the abundant presynaptic brain protein alpha-synuclein as fibrillary aggregates in neurons or glial cells is a hallmark lesion in a subset of neurodegenerative disorders. These disorders include Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy, collectively referred to as synucleinopathies. Importantly, the identification of missense mutations in the alpha-synuclein gene in some pedigrees of familial PD has strongly implicated alpha-synuclein in the pathogenesis of PD and other synucleinopathies. However, specific post-translational modifications that underlie the aggregation of alpha-synuclein in affected brains have not, as yet, been identified. Here, we show by mass spectrometry analysis and studies with an antibody that specifically recognizes phospho-Ser 129 of alpha-synuclein, that this residue is selectively and extensively phosphorylated in synucleinopathy lesions. Furthermore, phosphorylation of alpha-synuclein at Ser 129 promoted fibril formation in vitro. These results highlight the importance of phosphorylation of filamentous proteins in the pathogenesis of neurodegenerative disorders.

0 comments Cited 658 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with lewy bodies.

M Spillantini, R A Crowther, R. Jakes … (1998)

Lewy bodies and Lewy neurites are the defining neuropathological characteristics of Parkinson's disease and dementia with Lewy bodies. They are made of abnormal filamentous assemblies of unknown composition. We show here that Lewy bodies and Lewy neurites from Parkinson's disease and dementia with Lewy bodies are stained strongly by antibodies directed against amino-terminal and carboxyl-terminal sequences of alpha-synuclein, showing the presence of full-length or close to full-length alpha-synuclein. The number of alpha-synuclein-stained structures exceeded that immunoreactive for ubiquitin, which is currently the most sensitive marker of Lewy bodies and Lewy neurites. Staining for alpha-synuclein thus will replace staining for ubiquitin as the preferred method for detecting Lewy bodies and Lewy neurites. We have isolated Lewy body filaments by a method used for the extraction of paired helical filaments from Alzheimer's disease brain. By immunoelectron microscopy, extracted filaments were labeled strongly by anti-alpha-synuclein antibodies. The morphologies of the 5- to 10-nm filaments and their staining characteristics suggest that extended alpha-synuclein molecules run parallel to the filament axis and that the filaments are polar structures. These findings indicate that alpha-synuclein forms the major filamentous component of Lewy bodies and Lewy neurites.

0 comments Cited 597 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Parkinson's disease: a dual‐hit hypothesis

C Hawkes, K Del Tredici, H Braak (2007)

Accumulating evidence suggests that sporadic Parkinson's disease has a long prodromal period during which several non‐motor features develop, in particular, impairment of olfaction, vagal dysfunction and sleep disorder. Early sites of Lewy pathology are the olfactory bulb and enteric plexus of the stomach. We propose that a neurotropic pathogen, probably viral, enters the brain via two routes: (i) nasal, with anterograde progression into the temporal lobe; and (ii) gastric, secondary to swallowing of nasal secretions in saliva. These secretions might contain a neurotropic pathogen that, after penetration of the epithelial lining, could enter axons of the Meissner's plexus and, via transsynaptic transmission, reach the preganglionic parasympathetic motor neurones of the vagus nerve. This would allow retrograde transport into the medulla and, from here, into the pons and midbrain until the substantia nigra is reached and typical aspects of disease commence. Evidence for this theory from the perspective of olfactory and autonomic dysfunction is reviewed, and the possible routes of pathogenic invasion are considered. It is concluded that the most parsimonious explanation for the initial events of sporadic Parkinson's disease is pathogenic access to the brain through the stomach and nose – hence the term ‘dual‐hit’.

0 comments Cited 334 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Contributors

: +46-46-2220584 , +46-46-2220558 , Carla.lema_tome@med.lu.se

: +1-616-2345684 , +1-616-2345129 , patrik.brundin@vai.org

Journal

Journal ID (nlm-ta): Mol Neurobiol

Journal ID (iso-abbrev): Mol. Neurobiol

Title: Molecular Neurobiology

Publisher: Humana Press Inc (New York )

ISSN (Print): 0893-7648

ISSN (Electronic): 1559-1182

Publication date (Electronic): 29 April 2012

Publication date PMC-release: 29 April 2012

Publication date (Print): April 2013

Volume: 47

Issue: 2

Pages: 561-574

Affiliations

[ ]Neuronal Survival Unit, Wallenberg Neuroscience Center, Lund University, BMC B11, 221 84 Lund, Sweden

[ ]F. Hoffmann-La Roche Ltd, pRED, Pharma Research & Early Development, DTA CNS, Grenzacherstrasse 124, Basel, 4070 Switzerland

[ ]Center for Neurodegenerative Science, Van Andel Research Institute, 333 Bostwick Avenue NE, Grand Rapids, MI 49503 USA

Article

Publisher ID: 8267

DOI: 10.1007/s12035-012-8267-8

PMC ID: 3589652

PubMed ID: 22544647

SO-VID: e25a4069-c479-4987-ad08-e5b38ddb8d67

History

Date received : 7 February 2012

Date accepted : 4 April 2012

Custom metadata

ScienceOpen disciplines: Neurosciences

Keywords: dual-hit hypothesis,neuroinflammation,parkinson's disease,prion-like,proteinopathy,synucleinopathies,α-synuclein

Data availability:

ScienceOpen disciplines: Neurosciences

Keywords: dual-hit hypothesis, neuroinflammation, parkinson's disease, prion-like, proteinopathy, synucleinopathies, α-synuclein

Comments

Comment on this article

scite_

Smart Citations

Citing PublicationsSupportingMentioningContrasting

View Citations

See how this article has been cited at scite.ai

scite shows how a scientific paper has been cited by providing the context of the citation, a classification describing whether it supports, mentions, or contrasts the cited claim, and a label indicating in which section the citation was made.