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Restoration of Noradrenergic Function in Parkinson’s Disease Model Mice

Authors :
Kui Cui
Fan Yang
Turan Tufan
Muhammad U. Raza
Yanqiang Zhan
Yan Fan
Fei Zeng
Russell W. Brown
Jennifer B. Price
Thomas C. Jones
Gary W. Miller
Meng-Yang Zhu
Source :
ASN Neuro, Vol 13 (2021)
Publication Year :
2021
Publisher :
Taylor & Francis, 2021.

Abstract

Dysfunction of the central noradrenergic and dopaminergic systems is the primary neurobiological characteristic of Parkinson’s disease (PD). Importantly, neuronal loss in the locus coeruleus (LC) that occurs in early stages of PD may accelerate progressive loss of dopaminergic neurons. Therefore, restoring the activity and function of the deficient noradrenergic system may be an important therapeutic strategy for early PD. In the present study, the lentiviral constructions of transcription factors Phox2a/2b, Hand2 and Gata3, either alone or in combination, were microinjected into the LC region of the PD model VMAT2 Lo mice at 12 and 18 month age. Biochemical analysis showed that microinjection of lentiviral expression cassettes into the LC significantly increased mRNA levels of Phox2a, and Phox2b, which were accompanied by parallel increases of mRNA and proteins of dopamine β-hydroxylase (DBH) and tyrosine hydroxylase (TH) in the LC. Furthermore, there was considerable enhancement of DBH protein levels in the frontal cortex and hippocampus, as well as enhanced TH protein levels in the striatum and substantia nigra. Moreover, these manipulations profoundly increased norepinephrine and dopamine concentrations in the striatum, which was followed by a remarkable improvement of the spatial memory and locomotor behavior. These results reveal that over-expression of these transcription factors in the LC improves noradrenergic and dopaminergic activities and functions in this rodent model of PD. It provides the necessary groundwork for the development of gene therapies of PD, and expands our understanding of the link between the LC-norepinephrine and dopamine systems during the progression of PD.

Details

Language :
English
ISSN :
17590914
Volume :
13
Database :
Directory of Open Access Journals
Journal :
ASN Neuro
Publication Type :
Academic Journal
Accession number :
edsdoj.211b67322f2c43e6b811583451534260
Document Type :
article
Full Text :
https://doi.org/10.1177/17590914211009730