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Occurrence of α-synuclein pathology in the cerebellum of Guamanian patients with parkinsonism-dementia complex

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Abstract

Amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) is a progressive neurodegenerative disease affecting the indigenous Chamorro population of Guam. Neuropathologically, PDC is characterized by neuronal loss in the substantia nigra pars compacta with severe widespread neurofibrillary tangles (NFTs) similar to those observed in Alzheimer’s disease (AD), and is thus considered a tauopathy. Following reports of α-synuclein pathology in PDC patients of Guam, PDC has also been neuropathologically classified as a synucleinopathy. Recently, the presence of α-synuclein-positive bodies has been reported in the cerebellum of some patients with Parkinson’s disease (PD), diffuse Lewy body disease (DLBD), or multiple system atrophy (MSA). Using immunohistochemical techniques, we investigated the deposition of α-synuclein in the cerebellum of Guamanian PDC patients. Numerous α-synuclein-immunoreactive spherical structures were found in the molecular layer of the cerebellum of 63.6% of PDC patients. These structures were only seen in patients showing α-synuclein pathology in the amygdala. The average density of α-synuclein-immunoreactive structures in the cerebellum of Guamanian PDC patients was almost an order of magnitude higher than in non-Guamanian PD patients, and this α-synuclein pathology was much more pronounced in the hemisphere than in the vermis. In addition, double immunohistochemistry revealed that cerebellar α-synuclein is co-localized with the neuronal marker calbindin and with glial-fibrillary acidic protein, suggesting the involvement of Purkinje cells and Bergmann glia. These findings demonstrate that the α-synuclein pathology in PDC of Guam affects not only the amygdala, but also the cerebellum, where it appears to involve both Purkinje cells and specialized astrocytes.

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Acknowledgements

We thank the Chamorro patients and their families for making this research possible. A. Kapustin, C. Buitron, and W.G.M. Janssen provided expert technical assistance. Supported by NIH grants AG05138 and AG14382 to DPP and PRH.

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Authors and Affiliations

  1. Neuropathology Division, Department of Pathology, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1134, New York, NY , 10029, USA

    Joseph Sebeo & Daniel P. Perl

  2. Fishberg Research Center for Neurobiology and Kastor Neurobiology of Aging Laboratories, Mount Sinai School of Medicine, New York, USA

    Patrick R. Hof & Daniel P. Perl

  3. Department of Geriatrics and Adult Development, Mount Sinai School of Medicine, New York, USA

    Patrick R. Hof

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  1. Joseph Sebeo
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  2. Patrick R. Hof
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Correspondence to Daniel P. Perl.

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Sebeo, J., Hof, P.R. & Perl, D.P. Occurrence of α-synuclein pathology in the cerebellum of Guamanian patients with parkinsonism-dementia complex. Acta Neuropathol 107, 497–503 (2004). https://doi.org/10.1007/s00401-004-0840-4

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  • DOI: https://doi.org/10.1007/s00401-004-0840-4

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