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. 2024 Feb;50(1):e12962.
doi: 10.1111/nan.12962.

Inflammatory bowel disease induces pathological α-synuclein aggregation in the human gut and brain

Ana M Espinosa-Oliva  1   2 , Rocío Ruiz #  1   2 , Manuel Sarmiento Soto #  1   2   3 , Antonio Boza-Serrano #  1   2   4 , Ana I Rodriguez-Perez  5   6 , María A Roca-Ceballos  1   2 , Juan García-Revilla  1   2 , Marti Santiago  1   2 , Sébastien Serres  3   7 , Vasiliki Economopoulus  3 , Ana E Carvajal  8 , María D Vázquez-Carretero  8 , Pablo García-Miranda  8 , Oxana Klementieva  9 , María J Oliva-Martín  1   2 , Tomas Deierborg  4 , Eloy Rivas  10 , Nicola R Sibson  3 , José L Labandeira-García  5   6 , Alberto Machado  1   2 , María J Peral  8 , Antonio J Herrera  1   2 , José L Venero  1   2 , Rocío M de Pablos  1   2
Affiliations

Inflammatory bowel disease induces pathological α-synuclein aggregation in the human gut and brain

Ana M Espinosa-Oliva et al. Neuropathol Appl Neurobiol. 2024 Feb.

Abstract

Aims: According to Braak's hypothesis, it is plausible that Parkinson's disease (PD) originates in the enteric nervous system (ENS) and spreads to the brain through the vagus nerve. In this work, we studied whether inflammatory bowel diseases (IBDs) in humans can progress with the emergence of pathogenic α-synuclein (α-syn) in the gastrointestinal tract and midbrain dopaminergic neurons.

Methods: We have analysed the gut and the ventral midbrain from subjects previously diagnosed with IBD and form a DSS-based rat model of gut inflammation in terms of α-syn pathology.

Results: Our data support the existence of pathogenic α-syn in both the gut and the brain, thus reinforcing the potential role of the ENS as a contributing factor in PD aetiology. Additionally, we have analysed the effect of a DSS-based rat model of gut inflammation to demonstrate (i) the appearance of P-α-syn inclusions in both Auerbach's and Meissner's plexuses (gut), (ii) an increase in α-syn expression in the ventral mesencephalon (brain) and (iii) the degeneration of nigral dopaminergic neurons, which all are considered classical hallmarks in PD.

Conclusion: These results strongly support the plausibility of Braak's hypothesis and emphasise the significance of peripheral inflammation and the gut-brain axis in initiating α-syn aggregation and transport to the substantia nigra, resulting in neurodegeneration.

Keywords: Parkinson's disease; alpha-synuclein; inflammatory bowel disease; neurodegeneration; neuroinflammation.

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