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Cell type specific sequestration of choline acetyltransferase and tyrosine hydroxylase within Lewy bodies

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Abstract

Lewy bodies (LBs), the pathological hallmark of Lewy body disease (LBD), contain α-synuclein, as well as other proteins. In this study, we examined the relationship of α-synuclein to two rate-limiting enzymes in neurotransmitter synthesis, tyrosine hydroxylase (TH) and choline acetyltransferase (ChAT). Double-labeling immunohistochemistry for α-synuclein and TH revealed TH immunoreactivity within LBs in catecholaminergic neurons in the substantia nigra and locus coeruleus, but not within LBs in cholinergic neurons in the pedunculopontine nucleus and nucleus basalis of Meynert. In contrast, ChAT immunoreactivity within LBs was detected in cholinergic, but not within LBs in catecholaminergic neurons. The amygdala was devoid of TH and ChAT positive LBs, although a few Lewy neurites contained ChAT immunoreactivity. Further analysis revealed two distinct patterns of neurotransmitter immunoreactivity within LBs. One pattern had diffuse co-localization of TH or ChAT with α-synuclein as in cortical-type LBs, while the other had intense TH or ChAT immunoreactivity in the LB core surrounded by a peripheral rim of α-synuclein as in brainstem-type LBs. Levels of both TH and ChAT were higher in brainstem-type LBs than in the cytoplasm of the same neuron or in neurons from the same case devoid of LBs. Given the fact that LB-containing neurons have decreases in cytoplasmic TH and ChAT immunoreactivity, these results suggest LBs may disrupt cholinergic and catecholaminergic neurotransmitter production by sequestration of the rate-limiting enzymes for acetylcholine and catecholamine synthesis.

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Acknowledgments

The authors thank Monica Castanedes Casey, David Personett, Linda Rousseau and Virginia Phillips for their histopathological expertise and technical support. The authors would also like to thank Dr. Tanis Ferman for constructive advice. This research would not be possible without brain donations from patients and their families. This study was supported by grants from the National Institutes of Health (R01-AG15866, P50-AG16574, P50-NS40256) and Mayo Foundation for Research & Education.

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  1. Neuropathology Laboratory, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, FL, 32224, USA

    Brittany N. Dugger & Dennis W. Dickson

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  1. Brittany N. Dugger
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  2. Dennis W. Dickson
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Correspondence to Dennis W. Dickson.

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Dugger, B.N., Dickson, D.W. Cell type specific sequestration of choline acetyltransferase and tyrosine hydroxylase within Lewy bodies. Acta Neuropathol 120, 633–639 (2010). https://doi.org/10.1007/s00401-010-0739-1

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  • DOI: https://doi.org/10.1007/s00401-010-0739-1

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