Alpha-Synuclein in the Gastrointestinal Tract as a Potential Biomarker for Early Detection of Parkinson’s Disease

Abstract

The primary pathogenesis associated with Parkinson’s disease (PD) occurs in peripheral tissues several years before the onset of typical motor symptoms. Early and reliable diagnosis of PD could provide new treatment options for PD patients and improve their quality of life. At present, however, diagnosis relies mainly on clinical symptoms, and definitive diagnosis is still based on postmortem pathological confirmation of dopaminergic neuronal degeneration. In addition, the similarity of the clinical, cognitive, and neuropathological features of PD with other neurodegenerative diseases calls for new biomarkers, suitable for differential diagnosis. Alpha-synuclein (α-Syn) is a potential PD biomarker, due to its close connection with the pathogenesis of the disease. Here we summarize the currently available information on the possible use of α-Syn as a biomarker of early stages of PD in gastrointestinal (GI) tissues, highlight its potential to distinguish PD and other neurodegenerative diseases, and suggest alternative methods (primarily developed for other tissue analysis) that could improve α-Syn detection procedures or diagnostic methods in general.

The Neurodegenerative Elderly Syndrome (NES) hypothesis: Alzheimer and Parkinson are two faces of the same disease

“…These impairments are strongly related and influence each other. Many experimental and clinical studies have provided solid evidence supporting the early cellular and molecular alterations associated with the presence of αSyn aggregates and neurodegeneration before clinical manifestations ( Fricova et al, 2020 , Ghiglieri et al, 2018 , Twohig and Nielsen, 2019 ).…”

“…These trigger the neurodegenerative processes leading to AD and PD. In particular, enteric αSyn malfunctioning could mainly support the neurodegenerative trajectory leading to PD but not to AD ( Fricova et al, 2020 , Gold et al, 2013 ). The gut microbiota dysbiosis could instead contribute to producing initial monoamine dysfunctions leading to AD or PD ( Kowalski and Mulak, 2019 , Rani and Mondal, 2021 , Shabbir et al, 2021 ).…”

“…Hence, gastrointestinal αSyn could be used as a biomarker to distinguish PD and AD. Several new techniques can improve αSyn detection in gastrointestinal tissues ( Fricova et al, 2020 , Visanji et al, 2014 ). Among these, the nanoparticle-based methodologies, including sensor-based approaches, could be used to increase sensitivity ( Jang et al, 2020 , Kumar et al, 2020 ).…”

The Interplay between Gut Microbiota and Parkinson’s Disease: Implications on Diagnosis and Treatment

“…Since, as mentioned, GI symptoms often precede the onset of brain disorders, GM-based biomarkers have recently been considered as promising early and prodromal diagnostic tools in various neurological diseases, such as multiple sclerosis, AD and PD itself [ 30 , 156 , 157 ]. Concerning PD, it has been proposed that the severity of GI manifestations may be an early prediction of worse cognitive performances [ 158 ], and that the intestinal α-synuclein may function as a prodromal disease biomarker [ 159 ]. Moreover, GM composition might be used to monitor disease onset and progression [ 160 ].…”

Duodenal alpha-Synuclein pathology and enteric gliosis in advanced Parkinson’s Disease patients

“…Phosphorylated αSyn (p-αSyn) at Serine 129 residue, has been considered as the most reliable marker to distinguish pathological deposits from physiological protein. However, a consensus has not been reached so far on which antibody (anti-αSyn or anti-p-αSyn) should be used in peripheral tissues to distinguish PD patients from controls 9 19 20 , while antibodies specific for αSyn aggregates have been employed in a single study on colonic mucosa, with promising results 21 . Specifically, clone 5G4, the antibody used in this work can detect αSyn aggregates and it was raised against the sequence encompassing aminoacids 46-53 of αSyn 22 23 .…”