Udall Center - The University of Alabama at Birmingham

Udall Center - The University of Alabama at Birmingham

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

Title: Innate and Adaptive Immunity in Parkinson Disease

Website: https://www.uab.edu/medicine/udallp50/

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 reactive oxygen species (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 projects and three cores. Project 1 (Dr. David G. Standaert) examines 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) to determine whether there is evidence of systemic inflammatory response at earliest stages of PD. Project 2 (Dr. Etty “Tika” Benveniste) focuses 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

  • Project 1:  In collaboration with the Udall Center biostatistical and informatics support, Project 1 is pursuing completion of analysis of the blood monocyte samples collected under our prior P20 Exploratory Award. RNAseq data were obtained under the P20, but recently we have obtained Whole Genome Sequence (WGS) for these subjects through a collaboration with the public-private partnership, Accelerating Medicines Partnership for Parkinson's Disease (AMP PD). WGS is essential for full analysis of the monocyte RNAseq data, and we are moving ahead to complete this.
  •  Project 2: Current focus includes extensive analysis of T and B cell subsets in samples from the Udall cohort. Collaborative studies with Project 1 include an exploration of  the role of T cells in the rat synuclein pre-formed fibrils (PFF) model, derived from the Animal Models Core. This will be critical data for interpreting the results of the ongoing cohort studies. JAK1 inhibitors (Pfizer) have been validated for specificity, and poised for use in the rat fibril model of synucleinopathy. 
  • Project 3: Dr. Andrew West has relocated to Duke University, and has obtained new data on LRRK2 controlling Rab10-mediated signaling endosome recycling in mouse, rat, and human macrophages. New data suggest that LRRK2 phosphorylates Rab10 to shunt endosomes away from recycling or degradation to spur maturation into Rab7-positive vesicles. Through modification of these vesicles, LRRK2 mutations amplify signal transduction pathways relevant to alpha-synuclein stimulation of pro-inflammatory responses. Current work progresses to human LRRK2 mutation carrier primary cells and mosaic strains of rats with LRRK2 manipulated in immune cells.

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