Neuronal survival and function depends on largely on the nature of neuron-glia interactions. Previous work in our lab focused on identifying the cellular and signaling mechanisms required to promote neuronal survival and differentiation by the Glial-Derived Neurotrophic Factor Ligand (GFL) Family through the Ret tyrosine kinase/GFRalpha receptor complex which are expressed by various neuronal populations in the PNS (sensory, motor and parasympathetic ganglia) and in the CNS (dopaminergic and basal forebrain cholinergic neurons). While glia can provide trophic support and neuroprotection, certain neuron-glia interactions contribute to neuronal dysfunction and death. We have now turned our attention to understanding how glial-derived Tumor Necrosis Factor alpha(TNF), a potent neuroinflammatory mediator, regulates neuronal survival and/or death through its downstream targets.
Mechanisms of TNF-dependent neuroinflammation and neurotoxicity and their role in etiology and progression of neurodegenerative disease. A. Parkinsons?s Disease. Since post-mortem examination of SN from PD patients reveals a massive astrogliosis, the presence of activated microglial cells, and elevated levels of inflammatory cytokines, including Tumor Necrosis Factor (TNF), IL1b, IL-2, IL-4 and IL-6, our research is aimed at identifying the neurotoxic mechanisms associated with neuroinflammation and developing strategies to inhibit the glial reaction and/or targeting inflammatory cytokines which promote apoptosis and act to sustain the cycle of microglial-derived oxidative stress that elicits degeneration of ventral DA neurons and parkinsonism. Specifically, use of novel engineered TNF inhibitors (Steed, Tansey et al., Science (2003) 301:1895-1898) as biochemical tools has enabled us to identify soluble TNF-dependent mechanisms required for degeneration of dopamine neurons in several in vitro and in vivo models of PD. In addition, use of these dominant negative TNF inhibitors in neuroprotection studies in animal models of PD strongly suggests that targeting the TNF pathway may halt or slow the progressive degeneration of ventral midbrain DA neurons. Therefore, we are exploring the feasibility and efficacy of lentiviral delivery of DN-TNFs as proof of principle for further development of anti-TNF in vivo gene therapy approaches. Funding for these projects comes from the Michael J Fox Foundation of Parkinson?s Research.
B. Alzheimer?s Disease. The pro-inflammatory status of adult brain increases as we age and recent epidemiologic and clinical studies indicate that chronic use of non-steroidal anti-inflammatory drugs can lower the risk of developing neurodegenerative disease. Genetic mutations that result in abnormal processing of Amyloid Precursor Protein result in overproduction of neurotoxic amyloid beta peptides and formation of amyloid (senile) plaques, the hallmark of Alzheimer?s Disease. Given that increasing amyloid plaque burden correlates with cognitive decline and memory loss and plaque burden is influenced by the extent to which brain-resident microglia remove and deposit fibrillar Abeta as it forms with advancing age, our research is aimed at identifying the mechanisms by which TNF signaling positively or negatively regulates microglial activities and amyloid-beta associated neurotoxicity in normal and pathological conditions. Funding for this research comes from the Alzheimer?s Disease Center at UTSW and an Alzheimer?s Research grant from the American Health Assistance Foundation.
Our ultimate goal is to gain a better understanding of the mechanisms that contribute to neurodegeneration in order to develop new preventative or therapeutic interventions for the treatment of neurodegenerative diseases. Therefore, a new area of investigation for our lab entails investigating the cellular, molecular properties and neurorestorative potential of a stromal cell population from adult adipose which we term Adipose-Derived Adult Progenitor (ADAP) cells. Projects include investigating the developmental origins, the role of Notch signaling in neuro-glial fate induction and maturation of this progenitor population, their self-renewal/proliferation capacity, and the phenotypic stability of neurally differentiated ADAPs in vitro and in vivo after transplantation. Efforts are also aimed at assessing the therapeutic potential of ADAPs in lesion models (PD and SCI) and mechanisms by which they contributes to functional restoration of circuitry and normalize locomotor behavior. Funding for this research comes from the National Parkinson Foundation and the National Institutes of Health-NINDS.
Encinas M*, Tansey MG*, Tsui-Pierchala BA, Comella JX, Milbrandt J, Johnson EM Jr {* Equal authorship}, "c-Src is required for glial cell line-derived neurotrophic factor (GDNF) family ligand-mediated neuronal survival via a phosphatidylinositol-3 kinase (PI-3K)-dependent pathway." J Neurosci, 21(5):1464-72, March 2001
Steed PM, Tansey MG, Zalevsky J, Zhukovsky EA, Desjarlais JR, Szymkowski DE, Abbott C, Carmichael D, Chan C, Cherry L, Cheung P, Chirino AJ, Chung HH, Doberstein SK, Eivazi A, Filikov AV, Gao SX, Hubert RS, Hwang M, Hyun L, Kashi S, Kim A, Kim E, Kung J, Martinez SP, Muchhal US, Nguyen DH, O’Brien C, O’Keefe D, Singer K, Vafa O, Vielmetter J, Yoder SC, Dahiyat BI, "Inactivation of TNF signaling by rationally designed dominant-negative TNF variants." Science, 301(5641):1895-8, September 2003
Cheng HT, Miner JH, Lin M, Tansey MG, Roth K, Kopan R, "Gamma-secretase activity is dispensable for mesenchyme-to-epithelium transition but required for podocyte and proximal tubule formation in developing mouse kidney." Development, 130(20):5031-42, October 2003
Yang X, Tomita T, Wines-Samuelson M, Beglopoulos V, Tansey MG, Kopan R, Shen J, "Notch1 signaling influences v2 interneuron and motor neuron development in the spinal cord." Dev Neurosci, 28(1-2):102-17, 2006
McCoy MK, Martinez TN, Ruhn KA, Szymkowski DE, Smith CG, Botterman BR, Tansey KE, Tansey MG, "Blocking soluble tumor necrosis factor signaling with dominant-negative tumor necrosis factor inhibitor attenuates loss of dopaminergic neurons in models of Parkinson’s disease." J Neurosci, 26(37):9365-75, September 2006
SIGNIFICANT PUBLICATIONS
Yang X, Tomita T, Wines-Samuelson M, Beglopoulos V, Tansey MG, Kopan R, Shen J, "Notch1 signaling influences v2 interneuron and motor neuron development in the spinal cord." Dev Neurosci, 28(1-2):102-17, 2006
Steed PM, Tansey MG, Zalevsky J, Zhukovsky EA, Desjarlais JR, Szymkowski DE, Abbott C, Carmichael D, Chan C, Cherry L, Cheung P, Chirino AJ, Chung HH, Doberstein SK, Eivazi A, Filikov AV, Gao SX, Hubert RS, Hwang M, Hyun L, Kashi S, Kim A, Kim E, Kung J, Martinez SP, Muchhal US, Nguyen DH, O’Brien C, O’Keefe D, Singer K, Vafa O, Vielmetter J, Yoder SC, Dahiyat BI, "Inactivation of TNF signaling by rationally designed dominant-negative TNF variants." Science, 301(5641):1895-8, September 2003
McCoy MK, Martinez TN, Ruhn KA, Szymkowski DE, Smith CG, Botterman BR, Tansey KE, Tansey MG, "Blocking soluble tumor necrosis factor signaling with dominant-negative tumor necrosis factor inhibitor attenuates loss of dopaminergic neurons in models of Parkinson’s disease." J Neurosci, 26(37):9365-75, September 2006
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