Duodenal <scp>alpha‐Synuclein</scp> Pathology and Enteric Gliosis in Advanced Parkinson's Disease

Emmi, Aron; Sandre, Michele; Russo, Francesco Paolo; Tombesi, Giulia; Garrì, Federica; Campagnolo, Marta; Carecchio, Miryam; Biundo, Roberta; Spolverato, Gaya; Macchi, Verónica; Savarino, Edoardo; Farinati, Fabio; Parchi, Piero; Porzionato, Andrea; Bubacco, Luigi; De, Raffaele; Kovács, Gábor G.; Antonini, Angelo

doi:10.1002/mds.29358

Cited by 24 publications

(20 citation statements)

References 41 publications

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“…In previous studies, the conformation-specific 5G4 antibody yielded promising results in intestinal tissue. Indeed, this antibody has been used successfully to detect aSyn deposits in the colon and duodenal mucosa, yielding a sensitivity 83.3% and a specificity 88.2% in the colon, as well as a sensitivity of 100% and a specificity of 83.3% in the duodenum (15,16). In contrast to these data, we were unable to distinct between PD patients and controls on the basis of 5G4 or MJFR-14 immunoreactivity in rectal tissue.…”

Section: Discussionmentioning

confidence: 99%

Alpha-synuclein distribution and seeding activity in rectal biopsies in Parkinson’s disease

Kluge,

Kintrup,

Kulcsarova

et al. 2024

Preprint

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Background: Parkinson's disease (PD) is characterized by the accumulation of alpha-synuclein (aSyn) pathology, not only in the brain but also in the intestinal tissues. This study investigates the use of unique aSyn antibodies and an aSyn seed amplification assay (SAA) for detecting pathological aSyn in rectal biopsy samples from PD patients and healthy individuals. These samples were preserved using formalin-fixed and paraffin-embedded (FFPE) methods. Materials and Methods: The study analyzed the seeding capacity of FFPE submucosal rectal biopsies from 24 PD patients and 20 healthy controls using an aSyn SAA. It examined the distribution of aSyn using immunohistochemistry with antibodies targeting specific conformations and phosphorylated forms of aSyn at S129 and Y39. Additionally, the proximity-ligation assay was employed for phosphorylated S129 aSyn. Results: Pathological forms of aSyn were found in all FFPE biopsies from PD patients, as confirmed by SAA, and these were linked to the severity of motor symptoms (MDS-UPDRS-III). However, the immunoreactive patterns of conformation-specific or phosphorylated aSyn in rectal biopsies did not show notable differences between PD patients and healthy subjects. Conclusion: Pathological aSyn strains are detectable in FFPE rectal biopsies from PD patients with high accuracy using aSyn-SAA. However, the utility of immunohistochemical detection with current antibodies for identifying pathological aSyn forms appears limited. The findings advocate for the use of aSyn-SAA as a diagnostic tool for PD, contributing to a deeper understanding of the gut-brain connection in the disease.

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Section: Discussionmentioning

confidence: 99%

Alpha-synuclein distribution and seeding activity in rectal biopsies in Parkinson’s disease

Kluge,

Kintrup,

Kulcsarova

et al. 2024

Preprint

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show abstract

“…Methodological issues have posed great challenges, including the insufficient sensitivity and specificity of some α-synuclein immunohistochemical approaches for distinguishing PD patients from controls [ 21 ]. Still, there are studies that show promising results, such as a recent report of duodenal biopsies examined using the conformation-specific 5G4 α-synuclein antibody that preferentially detects aggregates [ 100 ]. This study found greater α-synuclein aggregation in PD cases compared with controls and detected pathology in both early- and late-stage PD patient biopsies [ 100 ].…”

Section: Discussionmentioning

confidence: 99%

“…Still, there are studies that show promising results, such as a recent report of duodenal biopsies examined using the conformation-specific 5G4 α-synuclein antibody that preferentially detects aggregates [ 100 ]. This study found greater α-synuclein aggregation in PD cases compared with controls and detected pathology in both early- and late-stage PD patient biopsies [ 100 ].…”

Section: Discussionmentioning

confidence: 99%

Gut-to-Brain α-Synuclein Transmission in Parkinson’s Disease: Evidence for Prion-like Mechanisms

Chen

Mor

2023

IJMS

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Parkinson’s disease (PD) is a multifactorial disorder involving both motor and non-motor symptoms caused by the progressive death of distinct neuronal populations, including dopaminergic neurons in the substantia nigra. The deposition of aggregated α-synuclein protein into Lewy body inclusions is a hallmark of the disorder, and α-synuclein pathology has been found in the enteric nervous system (ENS) of PD patients up to two decades prior to diagnosis. In combination with the high occurrence of gastrointestinal dysfunction in early stages of PD, current evidence strongly suggests that some forms of PD may originate in the gut. In this review, we discuss human studies that support ENS Lewy pathology as a characteristic feature of PD, and present evidence from humans and animal model systems that α-synuclein aggregation may follow a prion-like spreading cascade from enteric neurons, through the vagal nerve, and into the brain. Given the accessibility of the human gut to pharmacologic and dietary interventions, therapeutic strategies aimed at reducing pathological α-synuclein in the gastrointestinal tract hold significant promise for PD treatment.

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“…In the gut, ER stress mainly involves cells with high secretory phenotype, including PCs and GCs, leading to dysfunctional defense barrier, altered intestinal permeability and unbalanced composition of the gut microbiota 149 . In contrast, studies suggest that aggregation of neurodegenerative proteins occurs in the gut at different stages of neurodegenerative diseases, 150,151 as well as in sporadic cases of IBD 152 . Protein aggregates are involved in several pathological events including degeneration of nerve fibers in the enteric nervous system (ENS) and activation of inflammatory response with expression of inflammatory cytokines 153,154 .…”

Section: The Role Of Er Stress Along the Gut–brain Axismentioning

confidence: 99%

Endoplasmic reticulum stress: A possible connection between intestinal inflammation and neurodegenerative disorders

Vivacqua,

Mancinelli,

Leone

et al. 2024

Neurogastroenterology Motil

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BackgroundDifferent studies have shown the key role of endoplasmic reticulum (ER) stress in autoimmune and chronic inflammatory disorders, as well as in neurodegenerative diseases. ER stress leads to the formation of misfolded proteins which affect the secretion of different cell types that are crucial for the intestinal homeostasis.PurposeIn this review, we discuss the role of ER stress and its involvement in the development of inflammatory bowel diseases, chronic conditions that can cause severe damage of the gastrointestinal tract, focusing on the alteration of Paneth cells and goblet cells (the principal secretory phenotypes of the intestinal epithelial cells). ER stress is also discussed in the context of neurodegenerative diseases, in which protein misfolding represents the signature mechanism. ER stress in the bowel and consequent accumulation of misfolded proteins might represent a bridge between bowel inflammation and neurodegeneration along the gut‐to‐brain axis, affecting intestinal epithelial homeostasis and the equilibrium of the commensal microbiota. Targeting intestinal ER stress could foster future studies for designing new biomarkers and new therapeutic approaches for neurodegenerative disorders.

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Duodenal alpha‐Synuclein Pathology and Enteric Gliosis in Advanced Parkinson's Disease

Abstract: plete blood cell count-derived ratios can be useful biomarkers for neurological diseases.

Cited by 24 publications

References 41 publications

Alpha-synuclein distribution and seeding activity in rectal biopsies in Parkinson’s disease

Alpha-synuclein distribution and seeding activity in rectal biopsies in Parkinson’s disease

Gut-to-Brain α-Synuclein Transmission in Parkinson’s Disease: Evidence for Prion-like Mechanisms

Endoplasmic reticulum stress: A possible connection between intestinal inflammation and neurodegenerative disorders

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