The overall hypothesis that underlies the focus of this grant proposal is that chronic TH1/classical inflammation is critical for the progression of neurodegeneration in Parkinson's disease (PD) and Gulf War Illnesses (GWI) and other neurodegenerative diseases. There is strong evidence from the literature that inflammation and oxidative damage are observed in the brains of PD patients, GWI patients and patients with other neurodegenerative diseases, however a critical question is the interaction of neurons, glia and T cells. Furthermore, there is mounting evidence that an during aging, there is development of a hostile environment that makes therapeutics that may be effective in the young animal, less effective in the aged animal.
The aims of this proposal are designed to examine this process by following the progression of damage from wild-type (WT) ?-synuclein overexpressed in the substantia nigra via transduction with adeno-associated virus (AAV)9. We will study the role of inflammation in this model and determine if therapeutics effective in young animals are equally effective in the aged.
Specific Aim 1 : Hypothesis: CX3CL1 (fractalkine) is a chemokine important in neuronal glial interactions. We propose that a gene therapy approach to administering CX3CL1 is viable and will be effective against rAAV9-synuclein models of PD. We will further examine interactions of chemokine signaling and T cells via IL12. CX3CL1 is a cytokine important in neuronal glial communication, however there is debate concerning which form of CX3CL1 is neuroprotective, as there are reports of neurodegenerative actions. We will continue exploring this question using 3 AAV9 constructs of CX3CL1 that have differential processing. In addition, ongoing neurodegeneration in ?-SYN models involves a complex interaction of chemokine signals that regulate both innate immune cells and T cells. We have preliminary data that one action of CX3CL1 is to reduce IL12, and important regulator of TH1 immunity.
Specific Aim 2 : Hypothesis: Aging alters both the innate and adaptive immune system, thus will alter the efficacy of immune based therapies. As PD the majority of PD occurs in elderly subjects, it is critical to consider this with respect to therapeutic choices. We will examine if AAV9-CX3CL1 therapy is effective in the AAV9-?-SYN model PD in aged animals. WE know that microglia in aged rodents show predominantly M1 responses and have blunted M2 signaling. This may alter neuronal - glial-Tcell chemokine signaling. We will examine the effect of CX3CL1 treatment to alter microglial responses and interact with regulation of T cell populations.
Specific Aim 3 : ?-Synuclein neurotoxicity is increased when T cells are present and depends on T cell- microglia communication via chemokines. We further predict that T cells in aged rats will have altered patterns of migration, homing and survival. Evidence is mounting that T cells play an important role in neurodegeneration in concert with microglia and other antigen presenting cells. This has not been studied extensively in models of PD involving ?-synuclein, however one study suggests a correlation. We will investigate this in the athymic nude rat, and then determine which type of T cell is involved by replacing T cell subsets individually by adoptive transfer methods.
There is ample evidence that Parkinson's disease is a major debilitating disease that effects many veterans. This disorder and related Parkinsonian signs are associated with a significant risk of morbidity and mortality in elderly veterans. Furthermore, Gulf War Illness (GWI) has been associated with a similar phenotype and loss of dopamine cells in the substantia nigra. This set of neurodegenerative diseases decreases a veteran's ability to carry out normal tasks of daily living and becomes more debilitating. Understanding the underlying cause helps us design appropriate pharmacological therapies such as drugs that renew with the balance between neuro-inflammation and neural repair. If these therapies have significant clinical potential this will be a step forward for Parkinson's therapeutics.
|Grimmig, Beth; Daly, Lauren; Subbarayan, Meena et al. (2018) Astaxanthin is neuroprotective in an aged mouse model of Parkinson's disease. Oncotarget 9:10388-10401|
|Nash, Kevin R; Moran, Peter; Finneran, Dylan J et al. (2015) Fractalkine over expression suppresses ?-synuclein-mediated neurodegeneration. Mol Ther 23:17-23|
|Shahaduzzaman, Md; Nash, Kevin; Hudson, Charles et al. (2015) Anti-human ?-synuclein N-terminal peptide antibody protects against dopaminergic cell death and ameliorates behavioral deficits in an AAV-?-synuclein rat model of Parkinson's disease. PLoS One 10:e0116841|