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Cited by 5,415Parkinson's Disease Mechanisms and TreatmentsNeurological disorders and treatmentsNuclear Receptors and Signaling

Parkinson disease

Poewe, Werner, Seppi, Klaus, Tanner, Caroline M., Halliday, Glenda M., Brundin, Patrik, Volkmann, Jens, Schrag, Anette-Eleonore, Lang, Anthony E.·2017·Nature Reviews Disease Primers
DOI 10.1038/nrdp.2017.13
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Abstract

Parkinson disease is the second-most common neurodegenerative disorder that affects 2-3% of the population ≥65 years of age. Neuronal loss in the substantia nigra, which causes striatal dopamine deficiency, and intracellular inclusions containing aggregates of α-synuclein are the neuropathological hallmarks of Parkinson disease. Multiple other cell types throughout the central and peripheral autonomic nervous system are also involved, probably from early disease onwards. Although clinical diagnosis relies on the presence of bradykinesia and other cardinal motor features, Parkinson disease is associated with many non-motor symptoms that add to overall disability. The underlying molecular pathogenesis involves multiple pathways and mechanisms: α-synuclein proteostasis, mitochondrial function, oxidative stress, calcium homeostasis, axonal transport and neuroinflammation. Recent research into diagnostic biomarkers has taken advantage of neuroimaging in which several modalities, including PET, single-photon emission CT (SPECT) and novel MRI techniques, have been shown to aid early and differential diagnosis. Treatment of Parkinson disease is anchored on pharmacological substitution of striatal dopamine, in addition to non-dopaminergic approaches to address both motor and non-motor symptoms and deep brain stimulation for those developing intractable L-DOPA-related motor complications. Experimental therapies have tried to restore striatal dopamine by gene-based and cell-based approaches, and most recently, aggregation and cellular transport of α-synuclein have become therapeutic targets. One of the greatest current challenges is to identify markers for prodromal disease stages, which would allow novel disease-modifying therapies to be started earlier.

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Crossref · 10.1038/nrdp.2017.13

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  • Breid's study had a very small sample size, used an α-synuclein over-expressing model of PD which doesn't accurately capture the genotype of most PD patients (only 5-10% of PD patients have mutations in genes like SCNA, which encodes α-synuclein), and was subject to a confirmation bias because α-synuclein spread is more likely to be observed in α-synuclein over-expressing mice.

    “Despite this, Breid’s study had a very small sample size, used an α-synuclein over-expressing model of PD which doesn’t accurately capture the genotype of most PD patients (only 5–10% of PD patients have mutations in genes like SCNA, which encodes α-synuclein) [2], and was subject to a confirmation bias because α-synuclein spread is more likely to be observed in α-synuclein over-expressing mice.”

    From The gut–brain axis in early Parkinson’s disease: from prodrome to prevention (2025) · cites this paper as [2]

  • Progranulin is secreted into the extracellular space and taken up via the sortilin receptor for trafficking to the lysosome, where it is cleaved by lysosomal cathepsins into individual granulins or multi-granulin fragments.

    “Progranulin is secreted into the extracellular space and then taken up into cells via the sortilin receptor for trafficking to the lysosome, where it is cleaved by lysosomal cathepsins into individual granulins or multi-granulin fragments.131”

    From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [131]

  • Dopaminergic neuron loss in the substantia nigra along with a decline in dopamine released to the striatum constitutes the pathological PD hallmark.

    “Dopaminergic neuron loss in the substantia nigra along with a decline in dopamine (DA) released to the striatum constitutes the pathological PD hallmark [3].”

    From Neuroprotective Effects of Sodium Butyrate by Restoring Gut Microbiota and Inhibiting TLR4 Signaling in Mice with MPTP-Induced Parkinson’s Disease (2023) · cites this paper as [3]

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Authors
Poewe, W., Seppi, K., Tanner, C. M., Halliday, G. M., Brundin, P., Volkmann, J., Schrag, A.-E., & Lang, A. E.
Affiliations
  • Innsbruck Medical University (AT)
  • San Francisco VA Medical Center (US)
  • The University of Sydney (AU)
  • Van Andel Institute (US)
  • Universitätsklinikum Würzburg (DE)
  • UCL Queen Square Institute of Neurology (GB)
  • University of Toronto (CA)
Corresponding author
Poewe, Werner
ORCID
Venue
Nature Reviews Disease Primers
Publisher
Springer Science and Business Media LLC
Published
2017-03-23
Volume
3
Issue
1
Pages
17013-17013
ISSN
2056-676X (ISSN-L)
DOI
10.1038/nrdp.2017.13
OpenAlex
W4211044101
Cited by
5,415
References
20
Citations by year
2026: 687 · 2025: 808 · 2024: 771 · 2023: 737 · 2022: 675 · 2021: 667 · 2020: 526 · 2019: 277 · 2018: 202 · 2017: 57 · 2012: 2
FWCI
38.77
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Nature Reviews Disease Primers (publishedVersion)
  • PubMed (publishedVersion)
Funders
Parkinson's UK (K‐1213)
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, neurodegeneration, substantia nigra, dopamine deficiency, alpha-synuclein, Lewy bodies, non-motor symptoms, bradykinesia, neuroinflammation, mitochondrial dysfunction, oxidative stress, calcium homeostasis, axonal transport, neuroimaging biomarkers, dopamine replacement therapy, deep brain stimulation, gene therapy, cell therapy, prodromal Parkinson's disease, disease-modifying therapy
MeSH terms
Antiparkinson Agents, Humans, Levodopa, Mitochondria, Parkinson Disease, Quality of Life, Genetic Therapy, Biomarkers, Oxidative Stress, Dopamine Agonists, alpha-Synuclein

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