Stolzenberg E, Berry D, Yang, Lee EY, Kroemer A, Kaufman S, Wong GC, Oppenheim JJ, Sen S, Fishbein T, Bax A, Harris B, Barbut D, Zasloff MA. A Role for Neuronal Alpha-Synuclein in Gastrointestinal Immunity. J Innate Immun. 2017;9(5):456-463. Epub 2017 Jun 27 PubMed.
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Ottawa Hospital
The study by Stolzenberg and colleagues represents an important contribution to our understanding of environmental triggers of Parkinson’s pathogenesis. The authors have introduced a novel and welcome twist to the series of studies on gastrointestinal α-synuclein by investigating its expression in young patients, thereby obviating confounding age-related issues. They focus exclusively on the relationship between inflammation/infection and α-synuclein expression. The demonstration of a significant correlation between both acute and chronic inflammation and α-synuclein expression in the gut dovetails nicely with evidence, including that derived from genetic studies, for immune mechanisms in Parkinson’s pathogenesis. More importantly, the possible association with gut infection is interesting in the context of very exciting new research implicating α-synuclein as an antimicrobial peptide. This study also provides a hint regarding the temporal features of this phenomenon. By examining serial biopsies from transplanted patients, they suggest that inflammation-related changes in synuclein expression are indeed dynamic, and perhaps amenable to therapeutic modification. With respect to the transplanted patients however, what the α-synuclein staining represents is not entirely clear. Specifically, are we seeing host-derived synuclein-immunoreactive nerve fibers re-innervating the allograft or degenerating donor-derived fibers?
Finally, this study may provide an explanation for our observation that the most robust expression of α-synuclein in the gut can be found in the lamina propria of the vermiform appendix. The appendix is an immune organ whose wall is characterized by the presence of abundant lymphoid cells. It would be interesting to know whether increased α-synuclein expression in this organ is a cause or consequence of this. Of more direct relevance to the relationship between acute inflammation and α-synuclein staining shown by Stolzenberg and co-workers, it would be interesting to know whether appendectomy specimens showing appendicitis show elevated expression of α-synuclein. If, as the authors suggest, intestinal inflammation promotes α-synuclein expression and aggregation, is it possible that acute appendicitis represents a precursor to Parkinson’s disease? Unlikely, but this would certainly be an eerie coincidence considering that James Parkinson, with his son John, published one of the first clinical reports of acute appendicitis.
View all comments by John WoulfeGeorgetown
What an extraordinary insight, Dr. Woulfe! Your beautiful study showing the accumulation of α-synuclein in the appendix of neurologically normal subjects was remarkable (Gray et al., 2013) and we had included its reference in our initial drafts. What I took away from your story was the close apposition of macrophages to the α-synuclein-rich neurites, as well as your observation that those macrophages were chock full of α-synuclein. So it must be that one of the functions of the macrophage that has been attracted to the α-synuclein secreting neurite is garbage disposal work.
References:
Gray MT, Munoz DG, Gray DA, Schlossmacher MG, Woulfe JM. α-synuclein in the appendiceal mucosa of neurologically intact subjects. Mov Disord. 2013 Dec 18; PubMed.
View all comments by Michael ZasloffMake a Comment
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