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.
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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

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Figure 1

Screening PD-related proteins for autoantigenic T cell responses.

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Screening PD-related proteins for autoantigenic T cell responses. (A) Ex...
(A) Experimental design for the screening of PD-related proteins. (I) 15-mer peptides spanning PD-related proteins: PINK1 (117 peptides), PARKIN (94 peptides), OGDH (203 peptides), GBA (106 peptides), SOD1 (34 peptides), LRRK2 (80 predicted peptides), and PT as a control (132 peptides). (II) Peptide pools were incubated at a concentration of 5 ug/mL with PBMCs from PD participants and age-matched HCs for 14 days. (III) Restimulation of cultured PBMCs with the initial antigen pools and subsequent determination of antigen-specific cytokine production using Fluorospot. DMSO and PHA stimuli were used as negative and positive controls, respectively, for each participant/pool combination. (B) Magnitude of total cytokine response (sum of IFN-γ, IL-5, and IL-10) to neuroantigens and control PT between HCs (blue bars) and PD (red bars), each circle representing an individual participant. Median ± interquartile range displayed. Fold-change is in comparison to HC response. Two-tailed Mann-Whitney tests were performed between HC and PD antigen-cytokine values. Two-tailed Fisher’s exact tests were performed using the geometric mean of the HC group for each individual antigen as a cutoff for the test. PINK1 (PD, n = 39; HC, n = 39), PARKIN (PD, n = 37; HC, n = 39), OGDH (PD, n = 36; HC, n = 38), GBA (PD, n = 37; HC, n = 36), SOD1 (PD, n = 24; HC, n = 25), LRRK2 (PD, n = 26; HC, n = 24), and PT as a control (PD, n = 37; HC, n = 37). (C) Average percentage of cytokine of total response (i.e., IFN-γ/sum of IFN-γ/IL-5/IL-10) between HC and PD across all neuroantigens tested (PINK1, PARKIN, OGDH, GBA, SOD1, and LRRK2). Two-way ANOVA with Dunnett’s test.