Udall Center - University of Alabama at Birmingham

Udall Center - University of Alabama at Birmingham

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Director: David Standaert, M.D., Ph.D.

Title: Innate and Adaptive Immunity in Parkinson Disease

Website: https://www.uab.edu/medicine/udallp20/
 

Central Theme

The central hypothesis of the Alabama Udall Center is that innate and adaptive immune cells are activated early in Parkinson’s disease (PD), and that inhibiting their activities will protect from further PD-linked neurodegeneration. Current evidence suggests that accumulation of abnormal and/or misfolded α-synuclein (α-syn) is an early event in PD. Initially, α-syn is likely sequestered into inclusions in susceptible neurons. This state is reproduced by the α-syn fibril rat model used in our studies. In both human disease and α-syn based rodent models, neurons degenerate over time, and may release abnormal α-syn either through exocytic process (possibly including exosomes) or by necrosis and release of cell contents. Abnormal α-syn is a substrate for phagocytosis by brain microglia and a ligand for immune cell activation. The net effect of the presence of abnormal α-syn is that chemokines that can recruit peripheral immune cells and neurotoxic cytokines are produced in the brain. In both naïve monocytes and T-cells, the JAK/STAT pathway is a critical signal transduction pathway necessary for pro-inflammatory responses, resulting in an increase in damaging cytokines and ROS production. IFNɣ and IL-6 are canonical activators of JAK/STAT pro-inflammatory signaling in monocytes and T-cells. LRRK2 may be a key effector of the JAK/STAT axis as IFNγ activation of JAK/STAT signaling dramatically upregulates LRRK2 gene expression. JAK/STAT, and the effector LRRK2 protein, regulate monocyte/macrophage functions necessary for a robust pro-inflammatory response and the subsequent activation and differentiation of T-cells. Thus, we propose that a brain inflammatory response initiated by abnormal forms of α-syn and leading to the entry and pro-inflammatory differentiation of peripheral monocytes and T-cells is a key driver of the neurodegeneration which underlies both the motor and cognitive symptoms of PD.

Center Structure

The Alabama Udall Center consists of three project and three cores. Project 1 (Dr. David G. Standaert) will examine the role of innate immune cells in human PD by studying a cohort of patients with newly-diagnosed PD as well as age- and sex-matched controls. Project 2 (Dr. Etty “Tika” Benveniste) will focus on validating the JAK/STAT signaling pathway as a novel therapeutic strategy for treatment of PD. Project 3 (Dr. Andrew West) will focus on LRRK2 mediated macrophage responses in PD. An Administrative Core (Dr. Standaert) will provide coordination for the projects and facilitate communication, financial management, and manage compliance issues. This Core will also organize research career enhancement activities for Center investigators and periodic outreach to the PD patient/advocacy community. A Clinical Research Core (Dr. Talene Yacoubian) will be responsible for the recruitment of a cohort of 60 patients with newly-diagnosed PD and 60 age- and sex-matched controls. All subjects recruited will be followed longitudinally through annual assessments and biospecimen collections. The Animal Models Core (Dr. Laura Volpicelli-Daley) will ensure the animal models used in Projects 2 and 3 produce high quality data with minimal variability. This Core will purify and generate low endotoxin recombinant α-syn, generate fibrils and perform quality control assays, as well as perform stereotaxic injections and immunohistological analyses.

Recent Advances

The Alabama Udall Center has emerged as a result of a process of planning undertaken with support from an NINDS Exploratory Grant Program in Parkinson's Disease Research award (P20NS092530). A core premise for this award was the recognition that there are currently no Udall Centers of Excellence or other NIH-funded multi-investigator research programs focused on understanding neuroinflammatory mechanisms in PD. Through the support of the P20 Exploratory Award, we have accomplished key goals including: 1) solidifying a core collaborative team, incorporating experts in PD and others from outside the field; 2) developing and standardizing important models and methods; and 3) establishing a robust process to study immunomodulation in human subjects with early PD and in novel animal models. The Alabama Udall Center will bring this knowledge and skill in immune signaling in neurodegeneration to the Udall Centers network.

Public Health Statement

The development of new treatments to slow or prevent Parkinson disease (PD) is a vital unmet need. Recent work, including our studies through a P20 Exploratory Program award, have pointed to the critical role of neuroinflammation. The Alabama Udall Center involves an interactive team of investigators who will study both patients with PD and animal models of disease in order to facilitate the identification and development of treatments that target the immune system for neuroprotection in PD, to train next generation of scientists and physicians, and to communicate our work to the regional and national communities.

Budget End Date: 2023/07/31

NIH Grant Number: P50 NS108675