Enteric alpha‐synuclein expression is increased in <scp>P</scp>arkinson's disease but not <scp>A</scp>lzheimer's disease

Gold, Andrea; Turkalp, Zorbey; Muñoz, David G.

doi:10.1002/mds.25298

Cited by 108 publications

(116 citation statements)

References 38 publications

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“…Our observations are in line with Gray and colleagues, indicating that all neurologically intact subjects display αS-IR in their ganglion cell population [12]. Previous reports have reported αS-IR in none or in 8% to 82% of the neurologically intact subjects [11][12][13][14][15]. This discrepancy is related to the different antibodies used, different material assessed, i.e., surgical vs. post-mortem samples and the type of the sample, i.e., full thickness surgical sample vs. superficial endoscopic biopsy.…”

Section: Discussionsupporting

confidence: 93%

Neuronal Protein Alteration in Enteric Dysmotility Syndrome

Alafuzoff¹,

Popova²

2016

J Alzheimers Dis Parkinsonism

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Little is known about the enteric ganglionic system in subjects with gastrointestinal dysmotility syndrome (GIDS). Furthermore, dysfunction of gastrointestinal motility is an early complaint of subjects with Parkinson's disease.Here, we assessed p62/sequestosome-1(p62) and α-synuclein (αS) immunoreactivity (IR) in full-thickness bowel specimens of the gut obtained from six subjects with GIDS and from 17 controls.

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Section: Discussionsupporting

confidence: 93%

Neuronal Protein Alteration in Enteric Dysmotility Syndrome

Alafuzoff¹,

Popova²

2016

J Alzheimers Dis Parkinsonism

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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: 56%

“…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: 67%

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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“…Pathological α-synuclein proteins called Lewy bodies have long been known to aggregatein the enteric nervous system (ENS) of patients diagnosed with PD and NCDLB [1][2][3][4][5][6][7][8][9][10][11][12][13]. Specifically, in PD and NCDLB, Lewy bodies appear in the myenteric plexus (MP) and the colonic submucosal plexus (CSMP) [8,[14][15][16][17][18][19][20].…”

Section: Cholinergic Lewy Pathology In the Ensmentioning

confidence: 99%

“…Increasingly, cholinergic impairments in PD and NCDLB are attributed to Lewy Body pathology (Cholinergic impairment does not appear to be a consistent finding in Alzheimer's disease (AD) [27,42]. Research consistently demonstrates that autonomic dysfunction is a feature of PD and NCDLB, but not AD and that α-synuclein expression is increased in NCDLB and PD, but not in AD [2,7,9,[43][44][45][46]. For this reason, AD is not included in this discussion) [23,28,29].…”

Section: Cholinergic Lewy Pathology In the Ensmentioning

confidence: 99%

Mechanisms of α‐Synuclein Pathology and Treatment in the Enteric Nervous System

Lepkowsky¹

2017

IJGS

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Abstractα-synuclein (Lewy Body) pathology is commonly found in the enteric nervous system (ENS) of patients diagnosed with Neurocognitive Disorder with Lewy Bodies (NCDLB) and Parkinson's Disease (PD). Lewy pathology in the ENS can produce symptoms of bowel immotility, including constipation, obstipation, and bowel impaction. These symptoms significantly reduce the quality of life for the patient, producing hardship for the patient and care providers. In Lewy body patients, medical intervention using acetylcholinesterase inhibitors (AChEIs) can significantly reduce or alleviate bowel immotility. The specific mechanism through which the cholinergic agonist Donepezil mitigates Lewy Body bowel immotility is explained. Practice, 1143 Deer Trail Lane, Solvang, California 93463, USA, Tel: 805-688-1229 Fax: 805-686-9382; E-mail: clepkowsky@gmail.com of α-synuclein aggregates in the MP predates cognitive and motor functional manifestations of Lewy body diseases so consistently that it has been nominated as a potential biomarker for Lewy pathology [10,17,30]. Symptomatic Manifestations of Cholinergic Lewy Pathology in the ENSLewy body cholinergic impairment in the ENS manifests symptomatically as gastric immotility and constipation [13,[31][32][33][34][35][36][37][38][39][40][41]. Increased colonic transit time and impaired gastric emptying are frequently found in PD patients [35,42]. The prevalence of constipation in PD is at least three times that of the general population, leading some researchersto suggest that constipation might be a universal feature of PD [47,48]. Bowel immotility can occur 20 years before diagnosis of PD or NCDLB, suggesting that it might be a prodromal symptom for both disorders [5,19,36,44,[49][50][51][52].As α-synuclein pathology advances in the ENS, symptoms of gastric immotility advance from constipation to obstipation and impaction. Escalating gastric immotility in PD and NCDLB can interfere with mobility, sleep, cognition, and mood, increasing the cost of care, and potentially debilitating and/or dramatically reducing the quality of life for patients. [4,34,36,[53][54][55][56] Potential Exacerbation of ENS Symptoms by AntiParkinson MedicationLPD and NCDLB patients with significant Parkinsonian motoric/gait features are often prescribed L-dopa agents like Carbidopa-Levodopa (known also by the brand names Sinemet and Stalevo) in order to preserve gait, balance, and other basic motor functions [40,57,58]. Carbidopa-Levodopa's potential side effects include constipation [59]. which can complicate or exacerbate gastric immotility due to ENS Lewy pathology. Medications frequently used for the treatment of resting tremor in PD and NCDLB includeTrihexyphenidyl (marketed as Artane or Trihex) and Benztropinemesylate (marketed as Cogentin), identified as definite anticholinergics that can also exacerbate gastric immotility through suppression of the cholinergic neurotransmitter pathways innervating the ENS [58,[60][61][62].

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Enteric alpha‐synuclein expression is increased in Parkinson's disease but not Alzheimer's disease

Abstract: Either PD develops selectively in the enterically α-Syn-positive population subset or PD induces this expression. Absence of increased α-Syn expression in AD points to differences in pathogenesis.

Cited by 108 publications

References 38 publications

Neuronal Protein Alteration in Enteric Dysmotility Syndrome

Neuronal Protein Alteration in Enteric Dysmotility Syndrome

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

Mechanisms of α‐Synuclein Pathology and Treatment in the Enteric Nervous System

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