Alpha-synuclein immunoreactivity patterns in the enteric nervous system

Aldecoa, Ibán; Navarro‐Otano, Judith; Stefanova, Nadia; Sprenger, Fabienne; Seppi, Klaus; Poewe, Werner; Cuatrecasas, Míriam; Valldeoriola, Francesc; Gelpí, Ellen; Tolosa, Eduard

doi:10.1016/j.neulet.2015.07.005

Cited by 42 publications

(49 citation statements)

References 25 publications

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“…neuritic and ganglionic ) were considered to be specifically neuronal and putatively pathological. Different antibodies showed drastically different sensitivities (and specificities) for the neuronal pattern of staining, with the highest sensitivity being achieved with the O‐aSyn‐Ab, with a positive signal in 39% of PD vs. 24% HC, followed by the P‐aSyn‐Ab with 14% of PD vs. 24% HC, and finally T‐aSyn‐Ab that surprisingly, and in contrast with other studies 4, 15, 19, 20, 33 showed no neuronal staining in any of the examined cases. We found no difference in specificity whether we used O/P‐aSyn‐Ab.…”

Section: Discussionmentioning

confidence: 69%

“…Indeed, in addition to neurons, aSyn is physiologically expressed in hematopoietic 40, endothelial and neuroendocrine cells 41 and in muscle fibres 42. We found several cases with staining of epithelial cells of gastric glands that was considered to be a nondisease‐related cross‐reaction to some secretory protein or enzymes of the gastric mucosa 33. Cellular elements detected, on the other hand, could represent mucosal macrophages ingesting pathological aSyn but their role in PD pathogenesis remains to be established 18.…”

Section: Discussionmentioning

confidence: 88%

“…Varying sensitivity and specificity of aSyn antibodies recognizing different epitopes is a well‐described phenomenon in the brain 31, 32 but was recently also demonstrated in the GI tract 33. Harmonizing terminology used to describe different morphological patterns of aSyn immunoreactivity seen in the GI tract and their biological interpretation (pathological vs. nonspecific/physiological) is also emerging 33, 34. Similar to a recent consensus paper 34, we observed granular staining in the mucosa/lamina propria, which we termed as neuritic, since it is suggestive of localization in the peripheral nerve endings as demonstrated by staining with the neuronal marker (i.e.…”

Section: Discussionmentioning

confidence: 95%

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Detection of alpha‐synuclein conformational variants from gastro‐intestinal biopsy tissue as a potential biomarker for Parkinson's disease

Ruffmann

Bengoa-Vergniory

Poggiolini

et al. 2018

Neuropathology Appl Neurobio

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AimsGastrointestinal (GI) α‐synuclein (aSyn) detection as a potential biomarker of Parkinson's disease (PD) is challenged by conflicting results of recent studies. To increase sensitivity and specificity, we applied three techniques to detect different conformations of aSyn in GI biopsies obtained from a longitudinal, clinically well‐characterized cohort of PD patients and healthy controls (HC).MethodsWith immunohistochemistry (IHC), we used antibodies reactive for total, phosphorylated and oligomeric aSyn; with aSyn proximity ligation assay (AS‐PLA), we targeted oligomeric aSyn species specifically; and with paraffin‐embedded tissue blot (AS‐PET‐blot) we aimed to detect fibrillary, synaptic aSyn.ResultsA total of 163 tissue blocks were collected from 51 PD patients (113 blocks) and 21 HC (50 blocks). In 31 PD patients, biopsies were taken before the PD diagnosis (Prodromal); while in 20 PD patients biopsies were obtained after diagnosis (Manifest). The majority of tissues blocks were from large intestine (62%), followed by small intestine (21%), stomach (10%) and oesophagus (7%). With IHC, four staining patterns were detected (neuritic, ganglionic, epithelial and cellular), while two distinct staining patterns were detected both with AS‐PLA (cellular and diffuse signal) and with AS‐PET‐blot (aSyn‐localized and pericrypt signal). The level of agreement between different techniques was low and no single technique or staining pattern reliably distinguished PD patients (Prodromal or Manifest) from HC.ConclusionsOur study suggests that detection of aSyn conformational variants currently considered pathological is not adequate for the diagnosis or prediction of PD. Future studies utilizing novel ultrasensitive amyloid aggregation assays may increase sensitivity and specificity.

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Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 95%

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Detection of alpha‐synuclein conformational variants from gastro‐intestinal biopsy tissue as a potential biomarker for Parkinson's disease

Ruffmann

Bengoa-Vergniory

Poggiolini

et al. 2018

Neuropathology Appl Neurobio

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“…24,25 Varying sensitivity and specificity of antibodies were previously demonstrated in tissues from the gastrointestinal tract, 26 and the type of pretreatment also influences the final IHC result. Proteinase K pretreatment is highly effective in brain tissue 24 and yields up to 25-fold more detectable Lewy neurites.…”

Section: Methodological Considerationsmentioning

confidence: 98%

Pathological α‐synuclein in gastrointestinal tissues from prodromal Parkinson disease patients

Stokholm

Danielsen

Hamilton-Dutoit

et al. 2016

Annals of Neurology

334

262

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“…Mouse genetic models of PD pathogenesis also exhibit varying degrees of enteric neuronal dysfunction. α-synuclein is a member of a presynaptic family of synuclein proteins that are expressed widely in the nervous system 73–75 , including the ENS 20,76–78 . Synucleins can function as chaperone proteins and are necessary for neuronal survival 73 .…”

Section: Primary Disorders Of the Cnsmentioning

confidence: 99%

The bowel and beyond: the enteric nervous system in neurological disorders

Rao

Gershon

2016

Nat Rev Gastroenterol Hepatol

466

362

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The enteric nervous system (ENS) is large, complex and uniquely able to orchestrate gastrointestinal behaviour independently of the central nervous system (CNS). An intact ENS is essential for life and ENS dysfunction is often linked to digestive disorders. The part the ENS plays in neurological disorders, as a portal or participant, has also become increasingly evident. ENS structure and neurochemistry resemble that of the CNS, therefore pathogenic mechanisms that give rise to CNS disorders might also lead to ENS dysfunction, and nerves that interconnect the ENS and CNS can be conduits for disease spread. We review evidence for ENS dysfunction in the aetiopathogenesis of autism spectrum disorder, amyotrophic lateral sclerosis, transmissible spongiform encephalopathies, Parkinson disease and Alzheimer disease. Animal models suggest that common pathophysiological mechanisms account for the frequency of gastrointestinal comorbidity in these conditions. Moreover, the neurotropic pathogen, varicella zoster virus (VZV), unexpectedly establishes latency in enteric and other autonomic neurons that do not innervate skin. VZV reactivation in these neurons produces no rash and is therefore a clandestine cause of gastrointestinal disease, meningitis and strokes. The gut–brain alliance has raised consciousness as a contributor to health, but a gut–brain axis that contributes to disease merits equal attention.

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Alpha-synuclein immunoreactivity patterns in the enteric nervous system

Cited by 42 publications

References 25 publications

Detection of alpha‐synuclein conformational variants from gastro‐intestinal biopsy tissue as a potential biomarker for Parkinson's disease

Detection of alpha‐synuclein conformational variants from gastro‐intestinal biopsy tissue as a potential biomarker for Parkinson's disease

Pathological α‐synuclein in gastrointestinal tissues from prodromal Parkinson disease patients

The bowel and beyond: the enteric nervous system in neurological disorders

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