Disruption of Exocytosis in Sympathoadrenal Chromaffin Cells from Mouse Models of Neurodegenerative Diseases.

Diana Ortega-Cruz,Antonio G García,Antonio M G De Diego

doi:10.3390/ijms21061946

Abstract

Synaptic disruption and altered neurotransmitter release occurs in the brains of patients and in murine models of neurodegenerative diseases (NDDs). During the last few years, evidence has accumulated suggesting that the sympathoadrenal axis is also affected as disease progresses. Here, we review a few studies done in adrenal medullary chromaffin cells (CCs), that are considered as the amplifying arm of the sympathetic nervous system; the sudden fast exocytotic release of their catecholamines—stored in noradrenergic and adrenergic cells—plays a fundamental role in the stress fight-or-flight response. Bulk exocytosis and the fine kinetics of single-vesicle exocytotic events have been studied in mouse models carrying a mutation linked to NDDs. For instance, in R6/1 mouse models of Huntington’s disease (HD), mutated huntingtin is overexpressed in CCs; this causes decreased quantal secretion, smaller quantal size and faster kinetics of the exocytotic fusion pore, pore expansion, and closure. This was accompanied by decreased sodium current, decreased acetylcholine-evoked action potentials, and attenuated [Ca2+]c transients with faster Ca2+ clearance. In the SOD1G93A mouse model of amyotrophic lateral sclerosis (ALS), CCs exhibited secretory single-vesicle spikes with a slower release rate but higher exocytosis. Finally, in the APP/PS1 mouse model of Alzheimer’s disease (AD), the stabilization, expansion, and closure of the fusion pore was faster, but the secretion was attenuated. Additionally, α-synuclein that is associated with Parkinson’s disease (PD) decreases exocytosis and promotes fusion pore dilation in adrenal CCs. Furthermore, Huntington-associated protein 1 (HAP1) interacts with the huntingtin that, when mutated, causes Huntington’s disease (HD); HAP1 reduces full fusion exocytosis by affecting vesicle docking and controlling fusion pore stabilization. The alterations described here are consistent with the hypothesis that central alterations undergone in various NDDs are also manifested at the peripheral sympathoadrenal axis to impair the stress fight-or-flight response in patients suffering from those diseases. Such alterations may occur: (i) primarily by the expression of mutated disease proteins in CCs; (ii) secondarily to stress adaptation imposed by disease progression and the limitations of patient autonomy.

Highlights

Synaptic disruption and altered neurotransmitter release are common pathogenic features in neurodegenerative diseases (NDDs) such as Huntington’s disease (HD) [1], amyotrophic lateral sclerosis (ALS) [2], and in Alzheimer’s disease (AD) [3]
The alterations of bulk exocytosis, and the kinetics of single exocytotic events in chromaffin cells (CCs) from mouse models carrying a mutation of patients suffering from the NDDs described here, as well as those alterations elicited by pathological proteins associated with those diseases, support the hypothesis that “adrenal CCs and the sympathoadrenal axis controlling their functions, sense and mimic the alterations undergone by different synapses in the central nervous system (CNS) of patients with NDDs”
Peripheral sympathetic activity has been shown to have been altered in some NDDs, through the monitoring of the circulating levels of noradrenaline and adrenaline; scarce and controversial data have not drawn a clear picture

Summary

Introduction

Synaptic disruption and altered neurotransmitter release are common pathogenic features in neurodegenerative diseases (NDDs) such as Huntington’s disease (HD) [1], amyotrophic lateral sclerosis (ALS) [2], and in Alzheimer’s disease (AD) [3]. In amyotrophic lateral sclerosis (ALS), augmented glutamate release and glutamate receptors have been implicated in motoneuron death [9]. In this sense, it is worth noting that in the R6/2 mouse model of HD, brain dopamine release is severely compromised [10]. We will formulate a hypothesis on the potential impact of these alterations on the control of the stress fight-or-flight response by the sympathoadrenal axis in patients suffering HD, ALS, or AD

Central and Peripheral Control of the Stress Fight-or-Flight Response

Findings

Conclusions and Perspectives