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  • Review Article
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100 years of Lewy pathology

Abstract

In 1817, James Parkinson described the symptoms of the shaking palsy, a disease that was subsequently defined in greater detail, and named after Parkinson, by Jean-Martin Charcot. Parkinson expected that the publication of his monograph would lead to a rapid elucidation of the anatomical substrate of the shaking palsy; in the event, this process took almost a century. In 1912, Fritz Heinrich Lewy identified the protein aggregates that define Parkinson disease (PD) in some brain regions outside the substantia nigra. In 1919, Konstantin Nikolaevich Tretiakoff found similar aggregates in the substantia nigra and named them after Lewy. In the 1990s, α-synuclein was identified as the main constituent of the Lewy pathology, and its aggregation was shown to be central to PD, dementia with Lewy bodies, and multiple system atrophy. In 2003, a staging scheme for idiopathic PD was introduced, according to which α-synuclein pathology originates in the dorsal motor nucleus of the vagal nerve and progresses from there to other brain regions, including the substantia nigra. In this article, we review the relevance of Lewy's discovery 100 years ago for the current understanding of PD and related disorders.

Key Points

  • 100 years ago, Fritz Heinrich Lewy used light microscopy to describe the nerve cell inclusions that are characteristic of Parkinson disease (PD)

  • The Lewy pathology consists of the protein α-synuclein in an insoluble form

  • Missense and gene dosage mutations in SNCA, the α-synuclein gene, cause inherited cases of PD and dementia with Lewy bodies

  • In PD, α-synuclein pathology is widespread in the CNS and PNS

  • α-Synuclein pathology originates in a small number of nerve cells, from which it spreads in a prion-like fashion

  • Clinically, the development of the pathological changes of PD is reflected by the presence of nonmotor and motor symptoms

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Figure 1: 100 years of Lewy pathology: timeline of discoveries.
Figure 2: Members of Alois Alzheimer's research group at the Royal Psychiatric Clinic of the University of Munich, Germany in 1910.
Figure 3: Abnormal nerve cell bodies and processes in the dorsal motor nucleus of the vagal nerve in Parkinson disease.
Figure 4: Human α-synuclein and its disease-causing mutations.
Figure 5: Synuclein-immunoreactive Lewy pathology in the Parkinson disease brain.
Figure 6: Synuclein-immunoreactive Lewy pathology in the PD spinal cord, coeliac ganglion and gastrointestinal tract.
Figure 7: Six stages of PD pathology.
Figure 8: Stages 3–6 of Parkinson disease pathology.

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Acknowledgements

We thank Mrs Nathalie Cornée for tracking down references from times past. This article was supported in part by the UK Medical Research Council (U105184291), Parkinson's UK and the Deutsche Forschungsgemeinschaft (grant TR 1000/1-1).

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M. Goedert has received research support from Eli Lilly, and has acted as a consultant for GlaxoSmithKline and Hoffmann-La Roche. The other authors declare no competing interests.

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Goedert, M., Spillantini, M., Del Tredici, K. et al. 100 years of Lewy pathology. Nat Rev Neurol 9, 13–24 (2013). https://doi.org/10.1038/nrneurol.2012.242

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