Transgenic Mice Expressing Human a -Synuclein in Noradrenergic Neurons Develop Locus Ceruleus Pathology and Nonmotor Features of Parkinson ' s Disease

• Type of Material: Article
• Authors: Laura M Butkovich, Emory University; Madelyn Houser, Emory University; Termpanit Chalermpalanupap, Emory University; Kirsten A Porter-Stransky, Emory University; Alexa F Iannitelli, Emory University; Jake S Boles, University of Florida; Grace M Lloyd, University of Florida; Alexandra S Coomes, University of Florida; Lori N Eidson, Emory University; Maria Elizabeth Rodrigues, Emory University; Danielle L Oliver, Emory University; Sean Kelly, Emory University; Jianjun Chang, Emory University; Nora Bengoa-Vergniory, University of Oxford; Richard Wade-Martins, University of Oxford; Benoit I Giasson, University of Florida; Valerie Joers, University of Florida; David Weinshenker, Emory University; MariadeLourdes Tansey, Emory University
• Language: English
• Date: 2020-09-23
• Publisher: SOC NEUROSCIENCE
• Publication Version: Final Published Version
• Copyright Statement: © 2020 the authors
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1523/JNEUROSCI.1468-19.2020
• Title of Journal or Parent Work: JOURNAL OF NEUROSCIENCE
• Volume: 40
• Issue: 39
• Start Page: 7559
• End Page: 7576
• Grant/Funding Information: Further support was provided by the Georgia Clinical & Translational Science Alliance of the National Institutes of Health under Award Number UL1-TR-002378. In addition, this study was supported in part by the Emory HPLC Bioanalytical Core, which was supported by the Department of Pharmacology, Emory University School of Medicine and the Georgia Clinical & Translational Science Alliance of the National Institutes of Health under Award Number UL1-TR-002378. The content is solely the responsibility of the authors and does not necessarily reflect the official views of the National Institutes of Health.; This work was supported by National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS) Grant 5F31-NS-098673 (L.M.B.), NIH/NINDS Grant F32-NS-098615 (K.A.P.-S.), NIH/NINDS Grant 1R01-NS-102306 (D.W.), NIH/National Institute on Aging (NIA) Grant 1RF1-AG-047667 (D.W.), NIH/NIA Grant 1R01-AG-061175 (D.W.), NIH/NINDS Grant 1R01-NS-100876 (B.I.G.), NIH/NIA Grant 1R01-AG-057247 (M.G.T.), NIH/NINDS Grant 5R01-NS-092122 (M.G.T.), NIH/NIA Grant 3RF1-AG-051514-01 (M.G.T.), and the Norman Fixel Institute for Neurological Diseases (M.G.T.).; This research project was also supported in part by the Emory University Integrated Cellular Imaging Microscopy Core, and by the Rodent Behavioral Core (RBC), which is subsidized by the Emory University School of Medicine and is one of the Emory Integrated Core Facilities. Additional support was provided by the Emory Neuroscience NINDS Core Facilities Grant P30-NS-055077.
• Keywords: DOPAMINERGIC-NEURONS; COERULEUS; Parkinson's disease; locus ceruleus; OLFACTORY DYSFUNCTION; HUMAN ALPHA-SYNUCLEIN; Neurosciences & Neurology; norepinephrine; alpha-synuclein; nonmotor; Science & Technology; SUBSTANTIA-NIGRA; Life Sciences & Biomedicine; BRAIN; aging; MOTOR DEFICITS; MOUSE MODEL; Neurosciences; IN-VIVO; NOREPINEPHRINE
• Research Categories: Biology, Neuroscience; Biology, Physiology; Biology, Genetics

Abstract

Degeneration of locus ceruleus (LC) neurons and dysregulation of noradrenergic signaling are ubiquitous features of Parkinson's disease (PD). The LC is among the first brain regions affected by a-synuclein (asyn) pathology, yet how asyn affects these neurons remains unclear. LC-derived norepinephrine (NE) can stimulate neuroprotective mechanisms and modulate immune cells, while dysregulation of NE neurotransmission may exacerbate disease progression, particularly nonmotor symptoms, and contribute to the chronic neuroinflammation associated with PD pathology. Although transgenic mice overexpressing asyn have previously been developed, transgene expression is usually driven by pan-neuronal promoters and thus has not been selectively targeted to LC neurons. Here we report a novel transgenic mouse expressing human wild-type asyn under control of the noradrenergic-specific dopamine b-hydroxylase promoter (DBH-hSNCA). These mice developed oligomeric and conformation-specific asyn in LC neurons, alterations in hippocampal and LC microglial abundance, upregulated GFAP expression, degeneration of LC fibers, decreased striatal DA metabolism, and age-dependent behaviors reminiscent of nonmotor symptoms of PD that were rescued by adrenergic receptor antagonists. These mice provide novel insights into how asyn pathology affects LC neurons and how central noradrenergic dysfunction may contribute to early PD pathophysiology.