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Cited by 259Parkinson's Disease Mechanisms and TreatmentsNeurological disorders and treatmentsNuclear Receptors and Signaling

The α-Synuclein Origin and Connectome Model (SOC Model) of Parkinson’s Disease: Explaining Motor Asymmetry, Non-Motor Phenotypes, and Cognitive Decline

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Borghammer, Per·2021·Journal of Parkinson's Disease
DOI 10.3233/jpd-202481PMC PMC8150555
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Abstract

A new model of Parkinson’s disease (PD) pathogenesis is proposed, the α-Synuclein Origin site and Connectome (SOC) model, incorporating two aspects of α-synuclein pathobiology that impact the disease course for each patient: the anatomical location of the initial α-synuclein inclusion, and α-synuclein propagation dependent on the ipsilateral connections that dominate connectivity of the human brain. In some patients, initial α-synuclein pathology occurs within the CNS, leading to a brain-first subtype of PD. In others, pathology begins in the peripheral autonomic nervous system, leading to a body-first subtype. In brain-first cases, it is proposed that the first pathology appears unilaterally, often in the amygdala. If α-synuclein propagation depends on connection strength, a unilateral focus of pathology will disseminate more to the ipsilateral hemisphere. Thus, α-synuclein spreads mainly to ipsilateral structures including the substantia nigra. The asymmetric distribution of pathology leads to asymmetric dopaminergic degeneration and motor asymmetry. In body-first cases, the α-synuclein pathology ascends via the vagus to both the left and right dorsal motor nuclei of the vagus owing to the overlapping parasympathetic innervation of the gut. Consequently, the initial α-synuclein pathology inside the CNS is more symmetric, which promotes more symmetric propagation in the brainstem, leading to more symmetric dopaminergic degeneration and less motor asymmetry. At diagnosis, body-first patients already have a larger, more symmetric burden of α-synuclein pathology, which in turn promotes faster disease progression and accelerated cognitive decline. The SOC model is supported by a considerable body of existing evidence and may have improved explanatory power.

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Cited by

Sorted by citations

Authors
Borghammer, P.
Affiliations
Aarhus University Hospital (DK)
Corresponding author
Borghammer, Per
ORCID
Borghammer, Per
Venue
Journal of Parkinson's Disease
Publisher
SAGE Publications
Published
2021-04-13
Volume
11
Issue
2
Pages
455-474
ISSN
  • 1877-7171 (ISSN-L)
  • 1877-718X
DOI
10.3233/jpd-202481
PMC
PMC8150555
OpenAlex
W3134318550
Cited by
259
References
14
Citations by year
2026: 39 · 2025: 70 · 2024: 77 · 2023: 30 · 2022: 30 · 2021: 13
FWCI
4.81
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Parkinson s Disease (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Lundbeckfonden (R276‐2018‐294)
  • H. Lundbeck A/S
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Health Sciences › Medicine › Neurology › Neurological disorders and treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
Keywords
Parkinson's disease, alpha-synuclein, alpha-synuclein propagation, connectome, motor asymmetry, cognitive decline, amygdala, substantia nigra, dopaminergic neuron loss, vagus nerve, gut-brain axis, pathogenesis
MeSH terms
Synucleinopathies, Dopamine, Humans, Parkinson Disease, Phenotype, alpha-Synuclein, Cognitive Dysfunction, Connectome

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