Expression pattern and localization of alpha-synuclein in the human enteric nervous system

Böttner, Martina; Zorenkov, Dimitri; Hellwig, Ines; Barrenschee, Martina; Harde, Jonas; Fricke, Tobias; Deuschl, Günther; Egberts, Jan‐Hendrik; Becker, Thomas; Fritscher-Ravens, Annette; Arlt, Alexander; Wedel, Thilo

doi:10.1016/j.nbd.2012.07.018

Cited by 114 publications

(125 citation statements)

References 27 publications

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“…Each technique is specific for a particular variant or conformation of aSyn. For IHC, antibodies reactive for total (T‐aSyn‐Ab) and phosphorylated (P‐aSyn‐Ab) aSyn were selected as they have been most widely used for the detection of aSyn in the GI tract making our results comparable with these previous studies 4, 14, 15, 17, 19, 20. We also used recently developed antibodies specific for the oligomeric forms of aSyn (O‐ASN‐Abs) 26, as transformation of monomeric aSyn to oligomeric conformations is increasingly recognized as the early, key pathological event in the fibrillization process of aSyn 27.…”

Section: Introductionsupporting

confidence: 53%

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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: Introductionsupporting

confidence: 53%

“…Although phosphorylation is generally considered a marker of choice to delineate pathological aggregates from normal, native aSyn accumulation 35, using the P‐aSyn‐Ab, Bottner et al . 17 and Visanji et al . 19 detected neuronal aSyn pathology in all of their HC.…”

Section: Discussionmentioning

confidence: 94%

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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“…One study showed the presence of aSyn in individuals without PD in rectosigmoid segments obtained during partial colectomy in 13 of 13 subjects examined. 8 The same report found evidence of Ser129p-aSyn in 11 of 13 subjects without PD, associated with increasing age. In our study using PET blot, where aSyn was present, we also found Ser129p-aSyn in adjacent sections.…”

Section: Immunohistochemistry and Pet Blot Control Studiesmentioning

confidence: 88%

“…[5][6][7] However, the description of some degree of aSyn labeling in controls in these studies and reports of aSyn in colonic tissue from individuals without PD have raised concerns regarding specificity. 8,9 The aim of the present study was to optimize the immunohistochemical detection of aSyn in colonic biopsies by adapting the paraffin-embedded tissue (PET) blot, a method developed to increase sensitivity and specificity of detecting aggregated proteins in a related proteinopathy, Creutzfeldt-Jakob disease. The PET blot degrades nonaggregated proteins allowing the selective detection of remaining, presumably pathologic, protein aggregates.…”

Section: Methodsmentioning

confidence: 99%

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Colonic mucosal α-synuclein lacks specificity as a biomarker for Parkinson disease

et al. 2015

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Objective: To determine the utility of detecting a-synuclein (aSyn) in colonic mucosal biopsy tissue as a potential diagnostic biomarker for Parkinson disease (PD). Methods:We used the paraffin-embedded tissue (PET) blot, which degrades physiologic nonaggregated aSyn using proteinase K and enhances antigen retrieval allowing sensitive and selective detection of remaining protein aggregates, to detect aSyn in colonic mucosal biopsies from 15 patients with early PD (,3 years), 7 patients with later PD (.5 years), and 11 individuals without PD. aSyn and serine 129-phosphorylated aSyn (Ser129p-aSyn) were assessed by PET blot and conventional immunohistochemistry.Results: PET blot-resistant aggregated aSyn and Ser129p-aSyn was present in 12 of 15 individuals with early PD, 7 of 7 individuals with later PD, and 11 of 11 control subjects. The number of biopsies positive by PET blot relative to conventional immunohistochemistry was significantly lower in both PD groups compared with the control group for both aSyn and Ser129p-aSyn, whereas routine immunohistochemistry was positive more often in PD, but was positive in as many as 9 of 11 control individuals.Conclusion: Strong evidence of the presence of aggregated hyperphosphorylated aSyn in individuals with and without PD, using such a sensitive and specific method as the PET blot, suggests that colonic deposition of aSyn is not a useful diagnostic test for PD. The utility of detecting aSyn in the colon as a biomarker in combination with other assessments remains to be determined. An accurate diagnostic test for early or prodromal Parkinson disease (PD) is a significant unmet need. Studies suggesting that abnormal deposition of a-synuclein (aSyn) may originate in the peripheral autonomic nervous system, 1,2 coupled with evidence of a prion-like spread of synucleinopathy, 3 have generated much interest in evaluating enteric nervous system (ENS) aSyn to assess early PD neuropathology before disease spread and long before markers reliant on advanced disease are affected. 4 Several recent studies of aSyn staining in colonic tissue from living patients with PD report sensitivities ranging from 72% to a remarkable 100%. [5][6][7] However, the description of some degree of aSyn labeling in controls in these studies and reports of aSyn in colonic tissue from individuals without PD have raised concerns regarding specificity. 8,9 The aim of the present study was to optimize the immunohistochemical detection of aSyn in colonic biopsies by adapting the paraffin-embedded tissue (PET) blot, a method developed to increase sensitivity and specificity of detecting aggregated proteins in a related proteinopathy, Creutzfeldt-Jakob disease. The PET blot degrades nonaggregated proteins allowing the selective detection of remaining, presumably pathologic, protein aggregates.

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Associations of sleep characteristics with alpha‐synuclein in cerebrospinal fluid in older adults

Wang

Liu

et al. 2020

Ann Clin Transl Neurol

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Objective: Sleep disorders as a preclinical symptom of synucleinopathies become more prevalent in older adults. Synucleinopathies might be caused by the abnormal aggregation of alpha-synuclein in the brain, which was indicated by alpha-synuclein levels in cerebrospinal fluid (CSF). We aimed to investigate associations of sleep characteristics with CSF alpha-synuclein in older adults. Methods: Our study recruited 536 cognitively intact individuals (aged between 40 and 90 years old) from the Chinese Alzheimer's Biomarker and Lifestyle study. Sleep behaviors were assessed by Pittsburgh Sleep Quality Index and total alpha-synuclein in CSF was measured by enzyme-linked immune-sorbent assay. We used multiple linear and non-linear regression models for research. Results: Significant non-linear associations of CSF alpha-synuclein with sleep time and duration were revealed. Individuals who went to bed and fell asleep too early or late tended to have lower CSF alpha-synuclein (reflection point for time to bed and fall asleep were 10:26 p.m. and 10:40 p.m.). Lower CSF alpha-synuclein was also observed in individuals with either excessive or insufficient sleep duration (reflection point: 7.24 hours). Besides, overall poor sleep quality (b = À0.0621; P = 0.0242), longer sleep latency (b = À0.0415; P = 0.0174) and lower sleep efficiency (b = 0.0036; P = 0.0017) showed linear associations with lower CSF alpha-synuclein. Sleep disturbances and daytime dysfunction were not significantly associated with CSF alpha-synuclein. Interpretation: Poor sleep was associated with lower levels of CSF alpha-synuclein in older adults, which may provide new insight into the prevention of synucleinopathies.

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Expression pattern and localization of alpha-synuclein in the human enteric nervous system

Cited by 114 publications

References 27 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

Colonic mucosal α-synuclein lacks specificity as a biomarker for Parkinson disease

Associations of sleep characteristics with alpha‐synuclein in cerebrospinal fluid in older adults

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