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.

Keywords: LCO; PMCA; Parkinson’s disease; alpha-synuclein; biomarker; gastrointestinal tract; microRNA; oligomeric alpha-synuclein.

Figure 1

α-Syn structure, properties, and pathological forms. (A) Simplified scheme of α-Syn structure. α-Syn is a 140 aa protein, where the N-terminal and non-amyloid-β component (NAC) regions are responsible for its interaction with membrane structures. Mutations associated with Parkinson’s disease (PD) are located in the N-terminal region. The NAC region, the most hydrophobic part of the protein, is involved in random-coil conformational changes on the β -sheet. The unstructured C-region is responsible for the structural and physiological properties of the protein. The most discussed post-translational conditioning, phosphorylation at S129, is located in the C-terminal domain. (B) α-Syn is a cytoplasmic protein that occurs naturally as an unstructured monomer or metastable tetramer [49]. Under pathological conditions, its conformational changes occur from a random-coil to a beta-sheet structure to form unstable oligomers and protofibrils, followed by fibrils until insoluble protein aggregates are formed. These are localized in the neuronal soma (Lewy body) or in the neuronal processes (Lewy neurites).

Figure 2

α-Syn strains and their discrimination. Under pathological conditions, different types of α-Syn aggregates (strains), with specific biochemical, biophysical, and biological properties, occur in the brain of patients with various neurodegenerative diseases. It is the different properties of these strains that are responsible for the different clinical manifestations of these diseases. Differential diagnosis of PD and related neurodegenerative disorders is currently quite challenging. We propose several methods to discriminate such disorders, based on the specific physical and biochemical properties of α-Syn strains.

Figure 3

Alternative methods using gastrointestinal tract (GIT) tissues to detect α-Syn related pathogenesis and its strains discrimination. We propose a conventional immunohistochemical analysis (IHC) focused on the detection of pathological forms or the ratio between t-α-Syn and these forms instead of the detection of t-α-Syn. Similarly, miRNA profiling targeting specific disease-modulating miRNAs might be a relatively rapid tool for the detection of the early stages of the disease in GIT tissues (green boxes). Because different α-Syn strains are responsible for the diversity of clinical manifestations of neurodegenerative diseases, we propose several methods to distinguish these strains based on their specific physical and biochemical properties (blue boxes).