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Spectrum of abnormalities of sympathetic tyrosine hydroxylase and alpha-synuclein in chronic autonomic failure

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Abstract

Objective

Lewy body forms of primary chronic autonomic failure (CAF) such as incidental Lewy body disease (ILBD), Parkinson’s disease (PD), and pure autonomic failure evolving into dementia with Lewy bodies (PAF+DLB) feature cardiac sympathetic denervation, whereas multiple system atrophy (MSA) in most cases does not. What links Lewy bodies with cardiac sympathetic denervation in CAF? In familial PD, abnormalities of the alpha-synuclein (AS) gene cause CAF and cardiac sympathetic denervation; and in sporadic PD, brainstem Lewy bodies contain AS co-localized with tyrosine hydroxylase (TH), a marker of catecholaminergic neurons. Cytotoxicity from AS deposition within sympathetic neurons might explain noradrenergic denervation in Lewy body forms of CAF. We used immunofluorescence microscopy (IM) to explore this possibility in sympathetic ganglia obtained at autopsy from CAF patients.

Methods

Immunoreactive AS and TH were imaged in sympathetic ganglion tissue from 6 control subjects (2 with ILBD), 5 PD patients (1 with concurrent PSP), and 3 patients with CAF (2 PAF + DLB, 1 MSA).

Results

MSA involved normal ganglionic TH and no AS deposition. In ILBD TH was variably decreased, and TH and AS were co-localized in Lewy bodies. In PD TH was substantially decreased, and TH and AS were co-localized in Lewy bodies. In PAF + DLB TH was virtually absent, but AS was present in Lewy bodies. The PD + PSP patient had AS co-localized with tau but not TH.

Conclusions

Sympathetic denervation and intraneuronal AS deposition are correlated across CAF syndromes, consistent with a pathogenic contribution of synucleinopathy to cardiac noradrenergic deficiency in Lewy body diseases.

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Abbreviations

AS:

Alpha-synuclein

DA:

Dopamine

DOPAL:

3,4-Dihydroxyphenylacetaldehyde

ILBD:

Incidental Lewy body disease

IM:

Immunofluorescence microscopy

MSA:

Multiple system atrophy

NE:

Norepinephrine

OH:

Orthostatic hypotension

PAF + DLB:

Pure autonomic failure evolving into dementia with Lewy bodies

PD:

Parkinson’s disease

PSP:

Progressive supranuclear palsy

TH:

Tyrosine hydroxylase

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Acknowledgements

This research was supported by the Intramural Research Program of the NIH, National Institute of Neurological Disorders and Stroke. Dr. Isonaka is supported under a Japan Society for the Promotion of Science (JSPS) Postdoctoral Fellowship at NIH. We acknowledge Dr. Dragan Maric for mentoring Dr. Isonaka about multiplex immunofluorescence microscopy.

Funding

Division of Intramural Research, NINDS, NIH.

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Authors and Affiliations

  1. Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 10 Center Drive MSC-1620, Building 10 Room 8N260, Bethesda, MD, 20892-1620, USA

    Risa Isonaka, Patti Sullivan, Yunden Jinsmaa, Abraham Corrales & David S. Goldstein

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  1. Risa Isonaka
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  2. Patti Sullivan
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  3. Yunden Jinsmaa
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Correspondence to David S. Goldstein.

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The authors have no conflicts of interest to disclose.

Additional information

This manuscript is based on a presentation at the 28th International Symposium on the Autonomic Nervous System, November, 2017.

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Isonaka, R., Sullivan, P., Jinsmaa, Y. et al. Spectrum of abnormalities of sympathetic tyrosine hydroxylase and alpha-synuclein in chronic autonomic failure. Clin Auton Res 28, 223–230 (2018). https://doi.org/10.1007/s10286-017-0495-6

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  • DOI: https://doi.org/10.1007/s10286-017-0495-6

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