Evidence That Substantia Nigra Pars Compacta Dopaminergic Neurons Are Selectively Vulnerable to Oxidative Stress Because They Are Highly Metabolically Active.

Anjie Ni,Carl Ernst

doi:10.3389/fncel.2022.826193

Abstract

There are 400–500 thousand dopaminergic cells within each side of the human substantia nigra pars compacta (SNpc) making them a minuscule portion of total brain mass. These tiny clusters of cells have an outsized impact on motor output and behavior as seen in disorders such as Parkinson’s disease (PD). SNpc dopaminergic neurons are more vulnerable to oxidative stress compared to other brain cell types, but the reasons for this are not precisely known. Here we provide evidence to support the hypothesis that this selective vulnerability is because SNpc neurons sustain high metabolic rates compared to other neurons. A higher baseline requirement for ATP production may lead to a selective vulnerability to impairments in oxidative phosphorylation (OXPHOS) or genetic insults that impair Complex I of the electron transport chain. We suggest that the energy demands of the unique morphological and electrophysiological properties of SNpc neurons may be one reason these cells produce more ATP than other cells. We further provide evidence to support the hypothesis that transcription factors (TFs) required to drive induction, differentiation, and maintenance of midbrain dopaminergic neural progenitor cells which give rise to terminally differentiated SNpc neurons are uniquely involved in both developmental patterning and metabolism, a dual function unlike other TFs that program neurons in other brain regions. The use of these TFs during induction and differentiation may program ventral midbrain progenitor cells metabolically to higher ATP levels, allowing for the development of those specialized cell processes seen in terminally differentiated cells. This paper provides a cellular and developmental framework for understanding the selective vulnerability of SNpc dopaminergic cells to oxidative stress.

Highlights

Dopaminergic cells of the ventral midbrain that project to the striatum play an essential role in governing motor behavior in mammals
We review findings showing that substantia nigra pars compacta (SNpc) neurons are more vulnerable to oxidative phosphorylation (OXPHOS) insults than other dopaminergic cell types, discuss the morphological and electrophysiological properties of SNpc dopaminergic neurons that contribute to increasing adenosine triphosphate (ATP) demands
The evidence reviewed might suggest that SNpc cells require more ATP and more OXPHOS to sustain and maintain these particular functions than other cells and so are selectively vulnerable to genetic or metabolic insults, such as mutations in genes that support mitophagy or chemicals that interfere with Complex I of the electron transport chain

Summary

Anjie Ni and Carl Ernst*

Edited by: Alison Axtman, University of North Carolina at Chapel Hill, United States. Reviewed by: Martin Darvas, University of Washington, United States Matthew Wanat, University of Texas at San Antonio, United States. Specialty section: This article was submitted to Cellular Neurophysiology, a section of the journal

Dopaminergic Neurons Are Selectively Vulnerable to Oxidative

INTRODUCTION

Findings

CONCLUSION