Tansey Lab Research
- Mechanisms of TNF-dependent neuroinflammation and neurotoxicity and their role in etiology and progression of Parkinson’s and Alzheimer’s Disease (PD and AD).We aim to identify TNF-dependent signal transduction cascades and their molecular regulators underlying neuroinflammatory stress responses that promote programmed cell death and compromise neuronal survival in cell-based and animal models of neurodegeneration. A wealth of evidence arising from PET imaging studies, human autopsy samples, and animal models reveals massive astrogliosis, the presence of activated microglial cells, and elevated levels of inflammatory cytokines, including TNF, in brain regions most affected by these age-related neurodegenerative diseases. In addition, epidemiological studies suggest that chronic use of NSAIDs lowers the risk for developing either of these progressive neurodegenerative conditions, suggesting that inflammation may be contributing to neurodegeneration. We use novel engineered dominant-negative TNF inhibitors (McCoy et al., 2006; Barnum et al., 2014), viral vectors encoding DN-TNF sequences (McCoy et al., 2008; McAlpine et al., 2009; Harms et al., 2010), and other anti-inflammatory compounds (Tran et al., 2008) in pre-clinical models of PD- and AD-like pathology as tools to selectively target specific mediators (solTNF, NFkB, etc.) to investigate their role and signaling pathways via which they impact neuron-glia interactions, BBB and gut permeability, neuronal function and survival in vitro and in vivo. Our translational research efforts are aimed at identifying the neuroinflammatory and neurotoxic mechanisms that promote protein aggregation and dysregulated peripheral immune traffic to the CNS to hasten neuronal degeneration and death. The long-term goal of this line of investigation is to develop immunomodulatory therapeutic strategies to protect vulnerable neuronal populations and delay or prevent onset of neurodegenerative diseases like PD and AD. Funding for these projects comes from the Michael J. Fox Foundation of Parkinson’s Research, the Parkinson Disease Foundation, the Alzheimer’s Drug Discovery Foundation (ADDF), and the NIH/NINDS.
- Role of Regulator of G-protein Signaling-10 (RGS10) in neuroinflammation and immune responses that impact neuronal survival. Microglia, the brain’s resident macrophages, respond to immunological and environmental triggers and are critical to innate immune surveillance in the central nervous system (CNS). Additionally chronic activation of microglia, the hallmark of neuroinflammation, has been implicated in neurodegenerative diseases including Parkinson’s Disease (PD). Therefore, identification of molecular regulators of innate immunity and microglia activation will enhance our understanding of how neuroinflammatory mechanisms compromise neuronal survival/function. Our group discovered that Regulator of G-protein Signaling -10 (RGS10), a GTPase activating protein (GAP) enriched in microglia but also expressed in subsets of neurons, plays a critical role in regulating microglia activation and the outcome of neuroinflammatory responses in the brain, and that loss of RGS10 in mice increases the vulnerability to inflammation-induced degeneration of dopaminergic neurons (Lee et al., 2008). RGS10 regulates NFkB activation in microglia (Lee et al., 2011) and the M1/M2 balance in macrophages (Lee et al., 2012). These findings implicate RGS10 as an important regulator of innate immune function in the brain. New research projects in the lab are aimed at identifying molecular substrates of RGS10 in various immune cells, the molecular mechanism(s) and signaling pathways by which RGS10 regulates neuro-immune interactions in the CNS and gut, peripheral immune cell traffic to the CNS, and the extent to which aging and diseased states alter the levels or activity of RGS10 in rodents and humans and its implication in health and disease. Funding for these projects comes from The Michael J. Fox Foundation for Parkinson’s Research, Emory’s Parkinson’s Disease Collaborative Environmental Research Center (PD-CERC) and the NIH/NINDS.
- Role of common genetic variation (SNPs) in immune-related genes in determining risk for development and progression of neurodegenerative disease.Several single nucleotide polymorphisms (SNPs) in the gene cluster that encodes proteins that function in immune responses (in particular antigen presentation) have been reported to be associated with susceptibility to late-onset Parkinson’s disease (PD) or Alzheimer’s disease (AD) in genome-wide association studies (GWAS). One of the SNPs (rs3129882 initially referred to as PARK18) associated with late-onset PD is located within an intron of the HLA-DRA gene and together with other HLA SNPs in nearby regions of the MHC-II cluster that have also been associated with late-onset PD prompted us to investigate the role of antigen presentation. In collaboration with Drs. Jeremy Boss in the Immunology and Microbiology Department and Stewart Factor in the Movement Disorders Clinic at Emory University, we are conducting studies to elucidate the mechanism by which this particular SNP (rs3129882) is associated with risk for PD. We will examine the hypothesis that a high-risk allele (GG) at rs3129882 confers exacerbated or diminished immune responses. To determine if this genetic marker of PD is indicative of differential or misregulated HLA-DR gene expression (and subsequent changes in immune responses), immune cells isolated from the blood of PD patients and healthy volunteers will be compared. Immune cells from these individuals will be examined for expression of their HLA genes and a direct correlation between HLA-DR gene expression and disease will be made. Additionally, we will seek to determine if rs3129882 is predictive of a novel gene regulatory element or mechanism by determining the genetic regulatory activity of the DNA surrounding this region and examining ways in which this activity could be controlled, including an analysis of the epigenetic (non-DNA coding) patterns of inheritance associated with this region. If the hypothesis that the high risk allele (GG) genotype is predictive of exacerbated immune responses to neuronal injury associated with PD is correct, then development of distinct and novel diagnostic procedures may be possible to help predict onset, susceptibility, and rate of progression of this disease. Funding for these projects comes from The Michael J. Fox Foundation for Parkinson’s Research, Emory’s Parkinson’s Disease Collaborative Environmental Research Center (PD-CERC) and Emory’s Udall Center of Excellence for Parkinson’s Research funded by the NIH/NINDS.
- Gene-environment interactions and the role of chronic inflammatory disease in the etiology of neurodegenerative and neuropsychiatric disease. We have a long-standing interest in the interplay between genetic susceptibility and environmental factors now recognized to underlie the etiology of neurodegenerative disease and emerging as an important mechanism in neuropsychiatric and neurodevelopmental disorders. As such, we seek to develop ‘second-hit’ mouse models of disease in which a genetic deficiency is combined with an environmental stressor or exposure to investigate the function of a particular pathway in conferring susceptibility or protection against a specific stressor. Using this approach, we have discovered a role for Parkin in protection against systemic inflammation-related degeneration (Frank-Cannon et al., 2008). The long-term goal of these studies is to establish the extent to which various environmental factors (including psychological stress, peripheral inflammation, infections, metabolic syndrome, and obesity) endemic in the U.S. population trigger immune responses that enhance neuroinflammation, dysbiosis, and dysregulated peripheral immune cell traffic to the CNS thereby hastening neuronal dysfunction and leading to increased risk for neurodegenerative conditions and cognitive decline. Funding support for these studies comes from The Michael J. Fox Foundation for Parkinson’s Research, the Parkinson’s Disease Movement Foundation, and the Alzheimer’s Drug Discovery Foundatio
- Role of Leucine-Rich Repeat Kinase-2 (LRRK2) in immune cells and its relationship to idiopathic or familial Parkinson’s Disease pathogenesis. Mutations in the lrrk2 gene give rise to the most common form of dominantly-inherited parkinsonism and are associated with an estimated 1-2% of total PD cases with an incidence of 40% in the Ashkenazi Jewish PD population. While the majority of LRRK2 studies thus far have focused on its role in neurons, LRRK2 is abundantly expressed in cells of the immune system, including CD4+ and CD8+ T cells, CD14+ monocytes, and CD19+ B cells; yet its function in the immune system and the relationship of LRRK2 function in immune cells to PD pathogenesis is largely unknown. Therefore, studies in our lab seek to investigate the extent to which age-related alterations in LRRK2 levels or signaling function play a role in innate and adaptive immune cell mechanisms that increase vulnerability for idiopathic PD or accelerate the course of human disease. The short-term goal of these studies is to discover new aspects of LRRK2 biology in immune cells and identify genetic and/or environmental factors that trigger dysregulation of LRRK2 function in immune cells with the long-term goal of understanding how alterations in LRRK2 function may contribute to neurodegenerative disease pathogenesis and inform development of novel immunomodulatory therapies to treat PD. Funding support for these studies comes from The Michael J. Fox Foundation for Parkinson’s Research and the NIH/NINDS.
- Mechanisms of TNF-dependent neuroinflammation and neurotoxicity and their role in etiology and progression of depression. Depression is a common feature of Parkinson’s disease (PD) that is often present in the early pre-motor stages of the disease. Studies have reported an association between fatigue and depression in PD with elevated levels of circulating cytokines, including Tumor Necrosis Factor (TNF). In addition, Major Depressive Disorder (MDD) is one of the most disabling of all medical conditions worldwide with direct and indirect costs in the U.S. estimated to exceed $100 billion per year. The significance of this problem is reflected by the roughly 7 million depressed people that do not respond to classical anti-depressant treatment; termed treatment resistant depression (TRD) and suggests an alternative mechanism. Tumor Necrosis Factor (TNF) is reliably elevated in depressed patients and antagonism of TNF improves mood in patients with a variety of inflammatory diseases. A recent trial by our collaborators at Emory (Raison et al., 2013) demonstrated that a subset of TRD patients improved after treatment with the non-selective TNF antagonist infliximab. Moreover, plasma levels of the inflammatory c-reactive protein (CRP) >5mg/L predicted efficacy suggesting that CRP may be used as a biomarker. While these data are encouraging, use of infliximab and other commercially available non-selective TNF antagonists have significant liabilities; including an increased risk of immunosuppression and demyelinating neurologic disease. This occurs because these compounds inhibit both solTNF and transmembrane (tmTNF); solTNF drives chronic inflammatory disease while tmTNF facilitates host defense, synaptic plasticity, and myelination. XPro1595 is a novel, selective inhibitor of solTNF that readily crosses the BBB in therapeutic concentrations. We seek to establish preclinical proof-of-concept for XPro1595 as therapy for patients with TRD and increased inflammation. The efficacy of XPro1595 will be examined and directly compared to the commercially available anti-TNF drug etanercept in terms of efficacy and target engagement in a rodent model of stress-induced depression with increased inflammation. Successful completion of these studies will provide go/no go justification to proceed to a Phase II proof-of-concept clinical trial in TRD patients with elevated peripheral blood biomarkers. In support of this, XPro1595 currently has an open FDA IND for RA that is directly transferable in support of potential clinical trials in depression. Funding support for these studies comes from The Michael J. Fox Foundation for Parkinson’s Research and NIH/NIMH.
- The role of systemic inflammation in chronic disease and the risk for Alzheimer’s disease. Alzheimer’s disease – the most common age-related neurodegenerative disorder – is a personal and societal tragedy of immense and growing proportions. Over 5 million Americans currently suffer from Alzheimer’s disease (AD), and the number is expected to triple by 2050. Despite recent progress in characterizing AD, therapeutic intervention have been disappointing in large part because we lack a complete understanding of the mechanisms that contribute to this disease. Research suggests that peripheral inflammation is an important and modifiable risk factor for AD, and epidemiologic studies suggest that mid-life metabolic syndrome, obesity, and hypertension are inter-related health care conditions that increase the risk of age-related neurodegenerative disorders, particularly AD. The mechanistic links between these systemic disorders and neurodegeneration are poorly understood, but may be the key to developing effective anti-AD therapeutics. These risk factors are particularly prevalent in African Americans, who are also at increased risk for AD. The novel overarching hypothesis of this proposal is that chronic systemic disorders (i.e. metabolic syndrome and hypertension) are mechanistically linked to AD through a multistage process that involves dysregulation of the renin angiotensin system (RAS), systemic inflammation and a heightened peripheral immune response, followed by increased immune cell trafficking across the blood brain barrier (BBB) and leading to chronic neuroinflammation, CNS dysfunction, and cognitive decline. Studies are underway to answer the following questions: 1) What is the relationship between chronic peripheral inflammation and Alzheimer-like pathology in a transgenic mouse model of Alzheimer-like pathology?; 2) How is overactivation of the renin-angiotensin system related to brain inflammation, immune function and AD-like pathogenesis in this model?; and 3) How is RAS dysfunction related to central inflammation and immune function in humans at risk for AD? In addressing the third question we will focus on African Americans, who are particularly vulnerable to metabolic syndrome and AD yet have received little attention in systematic investigations. Successful completion of the proposed studies will provide new and potentially paradigm-shifting mechanistic information on how diet- and hypertension-induced chronic peripheral inflammation and chronic brain inflammation contribute to the development of AD. Funding support for these studies comes from the NIH/NIA.