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.

Espinosa-Oliva AM, Ruiz R, Soto MS, Boza-Serrano A, Rodriguez-Perez AI, Roca-Ceballos MA, García-Revilla J, Santiago M, Serres S, Economopoulus V, Carvajal AE, Vázquez-Carretero MD, García-Miranda P, Klementieva O, Oliva-Martín MJ, Deierborg T, Rivas E, Sibson NR, Labandeira-García JL, Machado A, Peral MJ, Herrera AJ, Venero JL, de Pablos RM. Inflammatory bowel disease induces pathological α-synuclein aggregation in the human gut and brain. Neuropathol Appl Neurobiol. 2024 Feb;50(1):e12962. doi: 10.1111/nan.12962. PMID: 38343067.


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