The impact of LRRK2 expression and kinase activity in gene by environment mouse models of Parkinson’s disease Público
Herrick, Mary (Spring 2020)
Published
Abstract
Extensive research has shown that Parkinson’s disease (PD) is a multifactorial disease with age, genetics, and environmental factors all contributing to risk for development of PD over an individual’s lifespan. The perfect combination of factors creates an environment in which peripheral and brain inflammation shift from protective to deleterious roles and promote PD pathogenesis. However, models exploring the multifaceted components of PD, especially in the context of one of the greatest genetic contributors to PD, Leucine-Rich Repeat Kinase 2 (LRRK2), in the immune system are vastly underexplored given that most PD LRRK2-related research has focused on the neuron. With the knowledge that LRRK2 is highly expressed in immune cells, the question of whether LRRK2 expression and phosphorylation regulates immune cell effector functions that then promote peripheral inflammation associated with PD and other immune diseases has now been brought to the forefront of the PD field.
We hypothesize that LRRK2 functions in immune cells to regulate effector functions and responses to inflammatory stress; but whether LRRK2 activation hastens protective or deleterious inflammatory responses when its levels increase in cells during inflammation remains to be determined, as do the effects of pathogenic LRRK2 mutations that increase risk for PD. To address this knowledge gap, in this doctoral dissertation we have utilized BAC transgenic LRRK2 mouse models overexpressing mouse wildtype LRRK2 or LRRK2 G2019S in all cells that endogenously express LRRK2. The aims of this research were to examine how 1) increased LRRK2 protein and or G2019S-dependent kinase activity affects immune cell profiles in vivo as a function of age; and 2) to investigate the extent to which specific environmental factors implicated in PD (bacterial and viral infections, colitis, and pesticides) act as second hits in the LRRK2 mice to promote PD-associated neuroinflammation and neuropathology. Here we report that increased LRRK2 protein or G2019S-dependent gain-of-function kinase activity does not alter immune cell profiles with aging. Additionally, we report that a second hit in the form of colitis, but not pesticides or bacterial and viral infections, in mice with increased mutant LRRK2 enhance neuroinflammation to promote neurotoxicity in the nigrostriatal pathway, resulting in PD-like neuropathology. Completion of the studies will advance our understanding of the role of LRRK2 in immune cells and alterations in the latter as a consequence of pathogenic mutations; such knowledge is a prerequisite to development of LRRK2-targeted therapeutics that will protect the brain without detrimental or untoward effects on immune system function in the fight against idiopathic and familial forms of PD.
Table of Contents
CHAPTER 1: BACKGROUND AND LITERATURE REVIEW
1.1: Parkinson’s disease…………………………………………………………………………………1
1.2: PD as a multifactorial disease…………………………………………………………………......2
1.2.1: Aging……………………………………………………………………………..…………….3
1.2.2: Genetics………………………………………………………………………..……………...3
1.2.3: Environmental exposures and lifestyles……………………………..……………………..4
1.3: The aging immune system………………………………………………………………………….6
1.4: Evidence for the immune system playing a role in PD pathogenesis………………………….7
1.4.1: Cellular evidence for inflammation playing a role in PD pathogenesis……..…………..8
1.4.1.1: Innate immunity – Microglia………………………………………………………..8
1.4.1.2: Innate immunity – Monocytes…………………………………………….………10
1.4.1.3: Adaptive immunity – T and B cells………………………………….…………...11
1.4.2: Epidemiological evidence linking the immune system and PD…………..…………….13
1.4.2.1: PD genetic susceptibility linked to immune-associated genes……………….13
1.4.2.2: Non-steroidal anti-inflammatory drugs…………………………………………..14
1.4.2.3: Autoimmune disorders…………………………………………………….………15
1.5: Leucine-Rich Repeat Kinase 2 (LRRK2) in PD…………………………………………………16
1.5.1: LRRK2 structure, function, and expression……………………..………………………..17
1.5.2: LRRK2 animal models……………………………………………..……………………….24
1.5.3: LRRK2 and the immune system………………………………………...…………………26
1.5.3.1: LRRK2 expression in brain-resident and peripheral blood immune cells……27
1.5.3.2: LRRK2 regulation of immune cell function……………………………………...28
1.5.3.3: LRRK2 in inflammation……………………………………………………………31
1.5.3.4: LRRK2 epidemiologically linked to inflammatory diseases…………………...33
1.5.3.5: LRRK2 association with bacterial infection models……………………………34
1.5.3.6: LRRK2 and -synuclein…………………………………………………………..35
1.6: Parkinson’s disease and the gastrointestinal system………………………………………….36
1.6.1: Non-motor symptoms linked to GI dysfunction…………………………………………..36
1.6.2: GI dysbiosis in PD…………………………………………………………………………...37
1.6.3: GI -synuclein pathology in PD……………………………………………………………38
1.6.4: Epidemiological evidence linking PD and IBD……………………………………………39
1.6.5: Similar phenotypes associated with PD and IBD………………………………………...41
1.6.6: LRRK2: linking PD and CD…………………………………………………………………42
1.6.7: Modeling colitis in animal models………………………………………………………….45
1.6.8: Evidence linking colitis and PD-associated neuropathology in animal models……….45
1.6.9: LRRK2 in colitis models…………………………………………………………………….48
1.7: Discussion…………………………………………………………………………………………..50
CHAPTER 2: LONGITUDINAL DEEP-IMMUNOPROFILING OF PERIPHERAL IMMUNE CELL SUBSETS IN WILDTYPE AND G2019S MUTANT LRRK2 BAC TRANSGENIC MICE
2.1: Abstract……………………………………………………………………………………………...52
2.2: Introduction………………………………………………………………………………………….53
2.3: Materials and Methods……………………………………………………………………………..55
2.4: Results………………………………………………………………………………………………59
2.5: Discussion…………………………………………………………………………………………..65
CHAPTER 3: INTESTINAL INFLAMMATION IN LRRK2 G2019S BAC TRANSGENIC MICE PROMOTES NEUROINFLAMMATION AND PD-ASSOCIATED NIGROSTRIATAL PATHOLOGY
3.1: Abstract………………….…………………………………………………………………………..69
3.2: Introduction………………………………………………………………………………………….70
3.3: Materials and Methods……………………………………………………………………………..73
3.4: Results………………………………………………………………………………………………83
3.5: Discussion…………………………………………………………………………………………..98
CHAPTER 4: THE EFFECTS OF LRRK2 AND CHRONIC PESTICIDE EXPOSURE IN WT OR G2019S OVEREXPRESSING MICE
4.1: Abstract…………………………………………………………………………………………….105
4.2: Introduction………………………………………………………………………………………..106
4.3: Materials and Methods……………………………………………………………………………108
4.4: Results……………………………………………………………………………………………..116
4.5: Discussion…………………………………………………………………………………………122
4.6: Acknowledgements……………………………………………………………………………….125
CHAPTER 5: THE EFFECTS OF VIRAL OR BACTERIAL INFECTION EXPOSURE IN WT OR G2019S OVEREXPRESSING MICE
5.1: Abstract…………………………………………………………………………………………….126
5.2: Introduction………………………………………………………………………………………..127
5.3: Materials and Methods……………………………………………………………………………129
5.4: Results……………………………………………………………………………………………..133
5.5: Discussion…………………………………………………………………………………………139
5.6: Acknowledgements……………………………………………………………………………….141
CHAPTER 6: DISCUSSION AND FUTURE DIRECTIONS
6.1: Summary…..………………………………………………………………………………………142
6.2: Discussion of results……………………………………………………………………………...142
6.3: Future directions…………………………………………………………………………………..143
6.4: Conclusions……………………………………………………………………………………….146
REFERENCES…………………………………………………………………………………………148
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