α-Synuclein seeding activity in duodenum biopsies from Parkinson's disease patients.

Autor: Vascellari, Sarah, Orrù, Christina D., Groveman, Bradley R., Parveen, Sabiha, Fenu, Giuseppe, Pisano, Giada, Piga, Giuseppe, Serra, Giulia, Oppo, Valentina, Murgia, Daniela, Perra, Andrea, Angius, Fabrizio, Hughson, Andrew G., Haigh, Cathryn L., Manzin, Aldo, Cossu, Giovanni, Caughey, Byron
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Zdroj: PLoS Pathogens; 6/30/2023, Vol. 18 Issue 6, p1-16, 16p
Abstrakt: Abnormal deposition of α-synuclein is a key feature and biomarker of Parkinson's disease. α-Synuclein aggregates can propagate themselves by a prion-like seeding-based mechanism within and between tissues and are hypothesized to move between the intestine and brain. α-Synuclein RT-QuIC seed amplification assays have detected Parkinson's-associated α-synuclein in multiple biospecimens including post-mortem colon samples. Here we show intra vitam detection of seeds in duodenum biopsies from 22/23 Parkinson's patients, but not in 6 healthy controls by RT-QuICR. In contrast, no tau seeding activity was detected in any of the biopsies. Our seed amplifications provide evidence that the upper intestine contains a form(s) of α-synuclein with self-propagating activity. The diagnostic sensitivity and specificity for PD in this biopsy panel were 95.7% and 100% respectively. End-point dilution analysis indicated up to 106 SD50 seeding units per mg of tissue with positivity in two contemporaneous biopsies from individual patients suggesting widespread distribution within the superior and descending parts of duodenum. Our detection of α-synuclein seeding activity in duodenum biopsies of Parkinson's disease patients suggests not only that such analyses may be useful in ante-mortem diagnosis, but also that the duodenum may be a source or a destination for pathological, self-propagating α-synuclein assemblies. Author summary: Misfolded α-Synuclein deposition is a hallmark of Parkinson's disease. The gastrointestinal tract may be an initial site of α-Synuclein aggregation, and its detection might be useful in the early diagnosis of Parkinson's disease. Here, we have used a rapid, ultrasensitive seed amplification assay (RT-QuICR) to show that pathologic α-Syn aggregates with prion-like self-propagating activity are in the upper intestine (duodenum) of Parkinson's disease patients. Our intra vitam detection of α-synuclein seeding activity in duodenum biopsies gave high diagnostic accuracy. Quantitation revealed high levels of seeds in duodenal tissue. Thus, our findings suggest that abnormal α-Synuclein seeds in the upper intestine might be both an early accurate biomarker for Parkinson's disease and cause of gut dysfunction. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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