Genetic lesions of the noradrenergic system trigger induction of oxidative stress and inflammation in the ventral midbrain

Justyna Barut; Katarzyna Rafa-Zabłocka; Agnieszka M Jurga; Monika Bagińska; Irena Nalepa; Rosanna Parlato; Grzegorz Kreiner

doi:10.1016/j.neuint.2022.105302

Genetic lesions of the noradrenergic system trigger induction of oxidative stress and inflammation in the ventral midbrain

Neurochem Int. 2022 May:155:105302. doi: 10.1016/j.neuint.2022.105302. Epub 2022 Feb 9.

Authors

Justyna Barut¹, Katarzyna Rafa-Zabłocka¹, Agnieszka M Jurga¹, Monika Bagińska¹, Irena Nalepa¹, Rosanna Parlato², Grzegorz Kreiner³

Affiliations

¹ Dept. Brain Biochemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, 31-343, Kraków, Smętna 12, Poland.
² Division of Neurodegenerative Disorders, Department of Neurology, Mannheim Center for Translational Neuroscience, Medical Faculty Mannheim Heidelberg University, Mannheim, Germany; Institute of Anatomy and Cell Biology, University of Heidelberg, 69120, Heidelberg, Germany. Electronic address: rosanna.parlato@medma.uni-heidelberg.de.
³ Dept. Brain Biochemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, 31-343, Kraków, Smętna 12, Poland. Electronic address: kreiner@if-pan.krakow.pl.

PMID: 35150790
DOI: 10.1016/j.neuint.2022.105302

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor deficits caused by the loss of dopaminergic neurons in the substantia nigra (SN) and ventral tegmental area (VTA). However, clinical data revealed that not only the dopaminergic system is affected in PD. Postmortem studies showed degeneration of noradrenergic cells in the locus coeruleus (LC) to an even greater extent than that observed in the SN/VTA. Pharmacological models support the concept that modification of noradrenergic transmission can influence the PD-like phenotype induced by neurotoxins. Nevertheless, there are no existing data on animal models regarding the distant impact of noradrenergic degeneration on intact SN/VTA neurons. The aim of this study was to create a transgenic mouse model with endogenously evoked progressive degeneration restricted to noradrenergic neurons and investigate its long-term impact on the dopaminergic system. To this end, we selectively ablated the transcription initiation factor-IA (TIF-IA) in neurons expressing dopamine β-hydroxylase (DBH) by the Cre-loxP system. This mutation mimics a condition of nucleolar stress affecting neuronal survival. TIF-IA^DbhCre mice were characterized by selective, progressive degeneration of noradrenergic neurons, followed by phenotypic alterations associated with sympathetic system impairment. Our studies did not show any loss of tyrosine hydroxylase (TH)-positive cells in the SN/VTA of mutant mice; however, we observed increased indices of oxidative stress, enhanced markers of glial cell activation, inflammatory processes and isolated degenerating cells positive for FluoroJade C. These results were supported by gene expression profiling of VTA and SN from TIF-IA^DbhCre mice, revealing that 34 out of 246 significantly regulated genes in the SN/VTA were related to PD. Overall, our results shed new light on the possible negative influence of noradrenergic degeneration on dopaminergic neurons, reinforcing the neuroprotective role of noradrenaline.

Keywords: Dopaminergic system; Neurodegeneration; Noradrenergic system; Parkinson's disease; Transcription factor TIF-IA.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Dopaminergic Neurons / metabolism
Inflammation / metabolism
Mesencephalon*
Mice
Norepinephrine / metabolism
Oxidative Stress
Substantia Nigra* / metabolism
Tyrosine 3-Monooxygenase / metabolism
Ventral Tegmental Area / metabolism

Substances

Tyrosine 3-Monooxygenase
Norepinephrine