The Impact of Mitochondrial Dysfunction on Dopaminergic Neurons in the Olfactory Bulb and Odor Detection

Thomas Paß,Rudolf J Wiesner,Sandra Blaess,Marlene Aßfalg,Markus Rothermel,Marianna Tolve,Konrad M Ricke

doi:10.1007/s12035-020-01947-w

Abstract

Understanding non-motor symptoms of Parkinson’s disease is important in order to unravel the underlying molecular mechanisms of the disease. Olfactory dysfunction is an early stage, non-motor symptom which occurs in 95% of Parkinson’s disease patients. Mitochondrial dysfunction is a key feature in Parkinson’s disease and importantly contributes to the selective loss of dopaminergic neurons the substantia nigra pars compacta. The olfactory bulb, the first olfactory processing station, also contains dopaminergic neurons, which modulate odor information and thereby enable odor detection as well as odor discrimination. MitoPark mice are a genetic model for Parkinson’s disease with severe mitochondrial dysfunction, reproducing the differential vulnerability of dopaminergic neurons in the midbrain. These animals were used to investigate the impact of mitochondrial dysfunction on olfactory-related behavior and olfactory bulb dopaminergic neuron survival. Odor detection was severely impaired in MitoPark mice. Interestingly, only the small anaxonic dopaminergic subpopulation, which is continuously replenished by neurogenesis, was moderately reduced in number, much less compared with dopaminergic neurons in the midbrain. As a potential compensatory response, an enhanced mobilization of progenitor cells was found in the subventricular zone. These results reveal a high robustness of dopaminergic neurons located in the olfactory bulb towards mitochondrial impairment, in striking contrast to their midbrain counterparts.

Highlights

Parkinson’s disease (PD) is the most common movement disorder affecting 1% of the population above 60 years [1] characterized by the initial loss of midbrain dopaminergic neurons (DaNs) in the substantia nigra pars compacta (SNc)
Sections immunostained for enhanced yellow fluorescent protein (EYFP)/tyrosine hydroxylase (TH) were imaged using with an inverted Zeiss AxioObserver Z1 microscope equipped with an ApoTome
Cells with respiratory chain deficits become apparent in olfactory bulb (OB) DaNs only in 30-week-old MitoPark mice (Fig. 2e), i.e. 28 weeks after TFAM inactivation at around P14, whereas midbrain DaNs uniformly present COX-deficiency already after weeks of age [39], i.e. weeks after TFAM inactivation at around E15.5

Summary

Introduction

Parkinson’s disease (PD) is the most common movement disorder affecting 1% of the population above 60 years [1] characterized by the initial loss of midbrain dopaminergic neurons (DaNs) in the substantia nigra pars compacta (SNc). The depletion of striatal dopamine leads to progressive and irreversible motor impairment [2]. Besides the cardinal symptoms of PD, non-motor dysfunctions including depression, sleep disturbance, and hyposmia have been described. Olfactory dysfunction is found in more than 95% of PD patients and can precede motor symptoms by up to 10 years [3,4,5].

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Conclusion