PINK1 is a target of T cell responses in Parkinson’s disease
Gregory P. Williams, … , Alessandro Sette, Cecilia S. Lindestam Arlehamn
Gregory P. Williams, … , Alessandro Sette, Cecilia S. Lindestam Arlehamn
Published December 17, 2024
Citation Information: J Clin Invest. 2025;135(4):e180478. https://doi.org/10.1172/JCI180478.
View: Text | PDF
Research Article Autoimmunity Immunology

PINK1 is a target of T cell responses in Parkinson’s disease

Abstract

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder. While there is no curative treatment, the immune system’s involvement with autoimmune T cells that recognize the protein α-synuclein (α-syn) in a subset of individuals suggests new areas for therapeutic strategies. As not all patients with PD have T cells specific for α-syn, we explored additional autoantigenic targets of T cells in PD. We generated 15-mer peptides spanning several PD-related proteins implicated in PD pathology, including glucosylceramidase β 1 (GBA), superoxide dismutase 1 (SOD1), PTEN induced kinase 1 (PINK1), Parkin RBR E3 ubiquitin protein ligase (parkin), oxoglutarate dehydrogenase (OGDH), and leucine rich repeat kinase 2 (LRRK2). Cytokine production (IFN-γ, IL-5, IL-10) against these proteins was measured using a fluorospot assay and PBMCs from patients with PD and age-matched healthy controls. We identified PINK1, a regulator of mitochondrial stability, as an autoantigen targeted by T cells, as well as its unique epitopes, and their HLA restriction. The PINK1-specific T cell reactivity revealed sex-based differences, as it was predominantly found in male patients with PD, which may contribute to the heterogeneity of PD. Identifying and characterizing PINK1 and other autoinflammatory targets may lead to antigen-specific diagnostics, progression markers, and/or novel therapeutic strategies for PD.

Authors

Gregory P. Williams, Antoine Freuchet, Tanner Michaelis, April Frazier, Ngan K. Tran, João Rodrigues Lima-Junior, Elizabeth J. Phillips, Simon A. Mallal, Irene Litvan, Jennifer G. Goldman, Roy N. Alcalay, John Sidney, David Sulzer, Alessandro Sette, Cecilia S. Lindestam Arlehamn

×

Figure 4

Identification of PINK1 epitopes eliciting T cell responses in PD.

Options: View larger image (or click on image) Download as PowerPoint
Identification of PINK1 epitopes eliciting T cell responses in PD. (A) E...
(A) Experimental design utilized to identify PINK1 epitopes. PINK1 megapool was used to expand previously identified PD PINK1 responders. A portion of megapool expanded cells for each participant were then restimulated with 10 PINK1 mesopools (smaller pools containing, on average, 12 individual PINK1 epitopes). The individual epitopes from the top 3 responding mesopools for each participant were then used to restimulate the remaining megapool expanded cells, allowing for the identification of individual antigenic PINK1 epitopes. (B) Individual PINK1 epitope responses (total cytokine, sum of IFN-γ, IL-5, IL-10) displayed in relation to the major regions of the PINK1 protein (left to right across amino acid 1–581; * at the x-axis for the peptide sequence indicates peptides that were also included as phosphorylated versions). The right graph displays phosphorylated peptides. Each dot is a participant/peptide combination. The response was considered positive when 3 criteria were met: (a) background-subtracted SFC/million cells above or equal to 100 SFC, (b) a fold-change of 2 or more compared with the negative control, and (c) a significant P value comparing triplicates for the negative control to the test triplicate. (C) Number of individual epitopes recognized by each of the 18 individual PD participants tested. (D) Individual cytokine responses (IFN-γ, IL-5, and IL-10) toward the 34 PINK1 epitopes displayed in order of frequency of recognition. Median ± interquartile range is shown.