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Cited by 285Parkinson's Disease Mechanisms and TreatmentsAlzheimer's disease research and treatmentsNuclear Receptors and Signaling

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The prion hypothesis in Parkinson's disease: Braak to the future

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Visanji, Naomi P, Brooks, Patricia L, Hazrati, Lili-Naz, Lang, Anthony E·2013·Acta Neuropathologica Communications
DOI 10.1186/2051-5960-1-2PMC PMC3776210
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Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder typified by the presence of intraneuronal inclusions containing aggregated alpha synuclein (αsyn). The progression of parkinsonian pathology and clinical phenotype has been broadly demonstrated to follow a specific pattern, most notably described by Braak and colleagues. In more recent times it has been hypothesized that αsyn itself may be a critical factor in mediating transmission of disease pathology from one brain area to another. Here we investigate the growing body of evidence demonstrating the ability of αsyn to spread transcellularly and induce pathological aggregation affecting neurons by permissive templating and provide a critical analysis of some irregularities in the hypothesis that the progression of PD pathology may be mediated by such a prion-like process. Finally we discuss some key questions that remain unanswered which are vital to determining the potential contribution of a prion-like process to the pathogenesis of PD.

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Figure 1 Staging of Lewy pathology according to the Braak model. Schematic summarizing the progression of Parkinson’s disease as proposed by Braak and colleagues [1]. According to the Braak model, αsyn deposits in specific brain regions and neuronal types giving rise to Lewy pathology in a stereotypic, temporal pattern that ascends caudo-rostrally from the lower brainstem (including the dorsal motor nucleus of the vagus nerve in the medulla then the coeruleus-subcoeruleus complex, raphe nuclei, gigantocellular reticular nucleus in the medulla aand pons) through susceptible regions of the midbrain (substantia nigra and the pedunculopontine tegmental nucleus) and forebrain (e.g., amygdala) and into the cerebral cortex (e.g., anteromedial temporal mesocortex, cingulate cortex and later neocortical structures). It is hypothesized that the disease initiates in the periphery, gaining access to the CNS through retrograde transport along projection neurons from the gastrointestinal tract. As the disease progresses, the severity of lesions in the susceptible regions increases.
Figure 1 Staging of Lewy pathology according to the Braak model. Schematic summarizing the progression of Parkinson’s disease as proposed by Braak and colleagues [1]. According to the Braak model, αsyn deposits in specific brain regions and neuronal types giving rise to Lewy pathology in a stereotypic, temporal pattern that ascends caudo-rostrally from the lower brainstem (including the dorsal motor nucleus of the vagus nerve in the medulla then the coeruleus-subcoeruleus complex, raphe nuclei, gigantocellular reticular nucleus in the medulla aand pons) through susceptible regions of the midbrain (substantia nigra and the pedunculopontine tegmental nucleus) and forebrain (e.g., amygdala) and into the cerebral cortex (e.g., anteromedial temporal mesocortex, cingulate cortex and later neocortical structures). It is hypothesized that the disease initiates in the periphery, gaining access to the CNS through retrograde transport along projection neurons from the gastrointestinal tract. As the disease progresses, the severity of lesions in the susceptible regions increases.CC BY · PubMed Central
Figure 2 Potential mechanisms of neuron-to-neuron transmission of synuclein. Alpha synuclein can be released into the extracellular space via (1) leakage from injured cells with compromised membrane integrity. Extracellular synuclein could then directly translocate the cell membrane and gain access to neighboring neurons (2). Synuclein can also be transmitted from cell-to-cell via conventional exocytosis and endocytosis (3). Synuclein can be packaged into exosomes which are released and taken up by surrounding cells (4).Tunneling nanotubes can form a direct connection between two cells potentially allowing synuclein to transfer freely from one cell to another (5). Finally, synuclein could be transmitted by direct synaptic contact (6).
Figure 2 Potential mechanisms of neuron-to-neuron transmission of synuclein. Alpha synuclein can be released into the extracellular space via (1) leakage from injured cells with compromised membrane integrity. Extracellular synuclein could then directly translocate the cell membrane and gain access to neighboring neurons (2). Synuclein can also be transmitted from cell-to-cell via conventional exocytosis and endocytosis (3). Synuclein can be packaged into exosomes which are released and taken up by surrounding cells (4).Tunneling nanotubes can form a direct connection between two cells potentially allowing synuclein to transfer freely from one cell to another (5). Finally, synuclein could be transmitted by direct synaptic contact (6).CC BY · PubMed Central

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Metadata

Authors
Visanji, N. P., Brooks, P. L., Hazrati, L.-N., & Lang, A. E.
Affiliations
  • Toronto Western Hospital (CA)
  • University of Toronto (CA)
Corresponding author
Lang, Anthony E
ORCID
Venue
Acta Neuropathologica Communications
Publisher
Springer Science and Business Media LLC
Published
2013-05-08
Volume
1
Issue
1
Pages
2-2
ISSN
2051-5960 (ISSN-L)
DOI
10.1186/2051-5960-1-2
PMC
PMC3776210
OpenAlex
W2159340140
Cited by
278
References
92
Citations by year
2026: 11 · 2025: 20 · 2024: 23 · 2023: 23 · 2022: 27 · 2021: 23 · 2020: 29 · 2019: 22 · 2018: 18 · 2017: 20 · 2016: 21 · 2015: 22 · 2014: 14 · 2013: 5
FWCI
2.69
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Acta Neuropathologica Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • TSpace (University of Toronto) (submittedVersion)
  • eScholarship@McGill (McGill) (submittedVersion, cc-by)
Topics
  • Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
Keywords
Parkinson's disease, prion hypothesis, alpha-synuclein, prion-like propagation, templating, Braak staging, neurodegeneration, alpha-synuclein aggregation, disease progression
MeSH terms
Animals, Humans, Models, Neurological, Parkinson Disease, Prions, Severity of Illness Index

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