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Transgenic mice expressing human alpha-synuclein in noradrenergic neurons develop locus coeruleus pathology and non-motor features of Parkinson’s disease

LM Butkovich, MC Houser, T Chalermpalanupap, KA Porter-Stransky, LN Eidson, ME De Sousa Rodrigues, DL Oliver, SD Kelly, J Chang, N Bengoa-Vergniory, R Wade-Martins, D Weinshenker, View ORCID ProfileMG Tansey
doi: https://doi.org/10.1101/857987
LM Butkovich
Department of Physiology, Emory School of Medicine, 30322
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MC Houser
Department of Physiology, Emory School of Medicine, 30322
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T Chalermpalanupap
Department of Human Genetics, Emory School of Medicine, 30322
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KA Porter-Stransky
Department of Human Genetics, Emory School of Medicine, 30322Department of Biomedical Sciences, Western Michigan University Homer Stryker M.D. School of Medicine, 49008
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LN Eidson
Department of Physiology, Emory School of Medicine, 30322
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ME De Sousa Rodrigues
Department of Physiology, Emory School of Medicine, 30322
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DL Oliver
Department of Physiology, Emory School of Medicine, 30322
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SD Kelly
Department of Physiology, Emory School of Medicine, 30322
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J Chang
Department of Physiology, Emory School of Medicine, 30322
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N Bengoa-Vergniory
Oxford Parkinson’s Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, UK OX1 3QX
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R Wade-Martins
Oxford Parkinson’s Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, UK OX1 3QX
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D Weinshenker
Department of Human Genetics, Emory School of Medicine, 30322
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MG Tansey
Department of Neuroscience and Center for Translational Research in Neurodegenerative Disease, University of Florida College of Medicine, 32610
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  • ORCID record for MG Tansey
  • For correspondence: mgtansey@ufl.edu
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Abstract

Degeneration of locus coeruleus (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 α-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 non-motor 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 β-hydroxylase promoter. These mice developed asyn aggregates in LC neurons, alterations in hippocampal and LC microglial abundance, upregulated GFAP expression, degeneration of LC fibers, decreased striatal dopamine metabolism, and age-dependent behaviors reminiscent of non-motor symptoms of PD. These mice provide novel insights into how asyn pathology affects LC neurons and how LC dysfunction may contribute to early PD pathophysiology.

Significance statement α-synuclein (asyn) pathology and loss of neurons in the locus coeruleus (LC) are two of the most ubiquitous neuropathologic features of Parkinson’s disease (PD). Dysregulated NE neurotransmission is associated with the non-motor symptoms of PD including sleep disturbance, emotional changes such as anxiety and depression, and cognitive decline. Importantly, loss of central NE may contribute to the chronic inflammation in, and progression of, PD. We have generated a novel transgenic mouse expressing human wild-type asyn in LC neurons to investigate how increased asyn expression affects the function of the central noradrenergic transmission and associated behaviors. We report cytotoxic effects of asyn overexpression associated with astrogliosis in the LC and LC target regions, degeneration of LC fibers with disruptions in striatal dopamine (DA) metabolism, and age-dependent alterations in non-motor behaviors.

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Posted November 28, 2019.
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Transgenic mice expressing human alpha-synuclein in noradrenergic neurons develop locus coeruleus pathology and non-motor features of Parkinson’s disease
LM Butkovich, MC Houser, T Chalermpalanupap, KA Porter-Stransky, LN Eidson, ME De Sousa Rodrigues, DL Oliver, SD Kelly, J Chang, N Bengoa-Vergniory, R Wade-Martins, D Weinshenker, MG Tansey
bioRxiv 857987; doi: https://doi.org/10.1101/857987
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Transgenic mice expressing human alpha-synuclein in noradrenergic neurons develop locus coeruleus pathology and non-motor features of Parkinson’s disease
LM Butkovich, MC Houser, T Chalermpalanupap, KA Porter-Stransky, LN Eidson, ME De Sousa Rodrigues, DL Oliver, SD Kelly, J Chang, N Bengoa-Vergniory, R Wade-Martins, D Weinshenker, MG Tansey
bioRxiv 857987; doi: https://doi.org/10.1101/857987

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