T cells recognise synuclein

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

David Sulzer (Columbia University), Roy Alcalay, Alessandro Sette and Cecilia Lindestam Arlehamn, with 20 co-authors (24 in all). Funders named in the paper: the JPB Foundation, the William F. Richter Fund and Parkinson's foundations, plus US National Institutes of Health grants.

What happened

Genetic studies had linked Parkinson's to variants in the HLA genes, which present protein fragments to T cells. The team exposed blood cells from 67 patients and 36 age-matched controls to alpha-synuclein fragments. Two regions drew responses: one near the start of the protein (called Y39) and one around position S129. The authors say the S129 response required the phosphorylated form, the form found in Lewy bodies; one commentator disputed that (Alzforum). Patients' T cells, both helper and killer types, responded strongly, controls little. About 40% of the patients responded. Responses to the Y39 region were tied to specific HLA variants, including DRB1*15:01 and DRB5*01:01. Nature 546:656–661, 21 June 2017; an erratum followed (Nature 549:292, 13 Sept 2017, DOI 10.1038/nature23896; its contents were not read). In 2020 the same group reported these T cells peak around and just before diagnosis and then decline (Nature Communications).

Why it moved us toward a cure

A genome-wide study had already tied Parkinson's risk to the HLA immune genes (landmark 195). Immune activation in the nigra had been seen since 1988 (landmark 52). This paper offered a mechanism for how synuclein could set off immune damage, and a reason for the HLA genetic signal. If T cells help kill neurons, then immune-modulating treatments could slow the disease. The paper itself has no animal experiments. It cites earlier mouse work showing killer T cells can kill neurons that display the right fragment, and that nigral cell death is absent in mice lacking MHC class II.

Outcome

Open. Commentators noted a small cross-sectional cohort, rare reactive cells, a strong genetic component, and uncertainty over whether T cells cause the damage or respond to it. Sources in this file report no immune-targeted therapy shown to help. The authors present it as a hypothesis to test.

Sources

• Sulzer et al., Nature 2017;546(7660):656–661, DOI 10.1038/nature22815, PMID 28636593 (abstract via Europe PMC; numbers, regions and funders from the author manuscript, PMC5626019)
• Erratum, Nature 2017;549:292, DOI 10.1038/nature23896
• Alzforum, "Trigger Warning: α-Synuclein Sets Off T Cells in Parkinson's" (independent comments)
• Newswise release, 21 Jun 2017
• Lindestam Arlehamn et al., Nat Commun 2020, DOI 10.1038/s41467-020-15626-w · ScienceDaily, Apr 2020
• Not yet verified: what the erratum corrects; all authors' institutions; whether any trial targets these T cells.