Transgenic mice expressing human alpha-synuclein in noradrenergic neurons develop locus coeruleus pathology and non-motor features of Parkinson's disease Restricted; Files Only

Butkovich, Laura (Summer 2019)

Permanent URL: https://etd.library.emory.edu/concern/etds/cf95jc458?locale=en
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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 the function and survival of these neurons remains unclear. LC-derived norepinephrine (NE) can stimulate neuroprotective mechanisms and modulate immune cells; therefore, we posit that dysregulation of NE neurotransmission may exacerbate PD progression, particularly non-motor symptoms, and contribute to the chronic neuroinflammation associated with PD pathology. Although transgenic mice overexpressing asyn have previously been developed to investigate the toxic effects of asyn accumulation on neuronal function and survival, 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 inclusions 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. This new mouse model will provide novel insights into how asyn pathology affects LC neurons and how LC dysfunction may contribute to early PD pathophysiology; and may serve as an important tool to screen drugs that may delay onset or slow progression of the disease.

Table of Contents

CHAPTER 1: BACKGROUND AND LITERATURE REVIEW

1.1: Parkinson’s Disease…………………………………………..….....1

1.2: Parkinson’s Disease Neuropathology……………………….….…2

1.3: ⍺-synuclein……………………………………………………..…….5

1.4: The Locus Coeruleus in Parkinson’s Disease……………………9

1.5: Potential mechanisms of Locus Coeruleus Degeneration in Parkinson’s disease…16

1.6: Neuroprotective and Immunomodulatory Effects of Norepinephrine……………....19

1.7: Norepinephrine and Peripheral Inflammation………….……..….22

1.8: Experimental Models of Parkinson’s Disease………….…..…….30

1.9: Discussion…………………………………………………..………..32

CHAPTER 2: THE CELLULAR AND PHYSIOLOGICAL IMPACTS OF HUMAN TYPE ALPHA-SYNUCLEIN COERULEUS NEURONS IN AN AGING ANIMAL MODEL

2.1: Abstract……………………………………………………………..34

2.2: Introduction…………………………………………………………35

2.3: Materials and Methods……………………………………………37

2.4: Results………………………………………………...……………44

2.5: Discussion……………………………………………...…………..65

CHAPTER 3: THE BEHAVIORAL EFFECTS OF HUMAN WILD-TYPE ALPHA-SYNUCLEIN EXPRESSION IN LOCUS COERULEUS NEURONS

3.1: Abstract……………………………………………………………....72

3.2: Introduction…………………………………………………...……...73

3.3: Materials and Methods………………………………………..…….76

3.4: Results………………………………………………………..……....80

3.5: Discussion…………………………………………..…………..……90

CHAPTER 4: DISCUSSION AND FUTURE DIRECTIONS

4.1 Summary…………………………………………………………...…94

4.2 Discussion of DBH-hSNCA model……………………………..…..94

4.3 Future directions…………………………….…………………….....95

4.4 Conclusions…………………………………………………………..100

REFERENCES……………………………..…………….…………..….101

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