Myelin Basic Protein and Cardiac Sympathetic Neurodegeneration in Nonhuman Primates.

Jeanette M Metzger,Heather A Simmons,Viktoriya Bondarenko,Alexandra D Zinnen,Kathryn M Jones,Marina E Emborg,Colleen F Moore,Helen N Matsoff,Don Vu,Jeff Bronstein

doi:10.1155/2021/4776610

Jeanette M Metzger, Heather A Simmons + Show 8 more

Open Access

https://doi.org/10.1155/2021/4776610

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Abstract

Minimal myelination is proposed to be a contributing factor to the preferential nigral neuronal loss in Parkinson's disease (PD). Similar to nigral dopaminergic neurons, sympathetic neurons innervating the heart have long, thin axons which are unmyelinated or minimally myelinated. Interestingly, cardiac sympathetic loss in PD is heterogeneous across the heart, yet the spatial relationship between myelination and neurodegeneration is unknown. Here, we report the mapping of myelin basic protein (MBP) expression across the left ventricle of normal rhesus macaques (n = 5) and animals intoxicated with systemic 6-OHDA (50 mg/kg iv) to model parkinsonian cardiac neurodegeneration (n = 10). A subset of 6-OHDA-treated rhesus received daily dosing of pioglitazone (5 mg/kg po; n = 5), a PPARγ agonist with neuroprotective properties. In normal animals, MBP-immunoreactivity (-ir) was identified surrounding approximately 14% of axonal fibers within nerve bundles of the left ventricle, with more myelinated nerve fibers at the base level of the left ventricle than the apex (p < 0.014). Greater MBP-ir at the base was related to a greater number of nerve bundles at that level relative to the apex (p < 0.05), as the percent of myelinated nerve fibers in bundles was not significantly different between levels of the heart. Cardiac sympathetic loss following 6-OHDA was associated with decreased MBP-ir in cardiac nerve bundles, with the percent decrease of MBP-ir greater in the apex (84.5%) than the base (52.0%). Interestingly, cardiac regions and levels with more MBP-ir in normal animals showed attenuated sympathetic loss relative to areas with less MBP-ir in 6-OHDA + placebo (r = −0.7, p < 0.014), but not in 6-OHDA + pioglitazone (r = −0.1) subjects. Our results demonstrate that myelination is present around a minority of left ventricle nerve bundle fibers, is heterogeneously distributed in the heart of rhesus macaques, and has a complex relationship with cardiac sympathetic neurodegeneration and neuroprotection.

Highlights

Cardiac sympathetic neurodegeneration is a common feature of Parkinson’s disease (PD) that may precede the hallmark nigral dopaminergic neuron loss and onset of motor symptoms characteristic of the disease [1]
E myelin marker myelin basic protein (MBP) was identified in myocardial nerve bundles throughout the left ventricle
MBP-ir spot distribution was diverse, with myelinated axons found near the perimeter or center of bundles, as individual spots or clusters, with no set pattern

Summary

Introduction

Cardiac sympathetic neurodegeneration is a common feature of Parkinson’s disease (PD) that may precede the hallmark nigral dopaminergic neuron loss and onset of motor symptoms characteristic of the disease [1]. It is a key component of cardiac dysautonomia and affects approximately 80% of PD patients. Dopaminergic neurons of the substantia nigra typically project into the striatum and have long, thin axons that are unmyelinated or have only a thin myelin sheath [7, 8]. Cardiac sympathetic axons emerge from the paravertebral sympathetic ganglia and travel as cardiac nerves before joining with parasympathetic fibers to form the cardiac plexus at the base of the heart [9]. A report analyzing myelination of sympathetic fibers in the anterior wall of the left ventricle found greater loss of unmyelinated compared to myelinated fibers in PD [10], suggesting that myelination may have a role in cardiac sympathetic neurodegeneration in PD

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