Functional and molecular early enteric biomarkers for Parkinson’s disease in mice and men

Abstract

Parkinson's disease (PD) usually has a late clinical onset. The lack of early biomarkers for the disease represents a major challenge for developing timely treatment interventions. Here, we use an -synuclein-overexpressing transgenic (Th-1-SNCA-A30P) mouse model of PD to identify appropriate candidate markers in the gut for early stages of PD before hallmark symptoms begin to manifest. A30P mice did not show alterations in gait parameters at 2 months of age, and these mice were therefore defined as pre-symptomatic A30P mice (psA30P). We discovered early functional motility changes in the gut and early molecular dysregulations in the myenteric plexus of psA30P mice by comparative protein and miRNA profiling and cell culture experiments. We found that the proteins neurofilament light chain, vesicle-associated membrane protein 2 and calbindin 2, together with the miRNAs that regulate them, are potential biomarkers of early PD that may facilitate timely treatment and/or prevention of PD in men.

Distinct patterns of gene expression changes in the colon and striatum of young mice overexpressing alpha-synuclein support Parkinson Disease as a multi-system process

“…Two other studies have used unbiased approaches to evaluate the gut in mouse models of PD and showed functional enrichment of terms and pathways similar to those in our study, such as protein ubiquitination [95], oxidative or cellular stress [95,96], and apoptosis [96]. One study used a proteomic approach to look at the prodromal phase of PD in a mutated aSyn overexpression model (Thy1-SNCA-A30P) [95]. Of proteins differentially expressed in the colon, 138 were encoded by genes that were detected in our study and 115 were matched in direction of dysregulation (Table S15, see Supplement 1).…”

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

“…In line with these claims and given that miRNAs are also present in GIT and ENS tissue, a recent study clearly shows the potential of miRNA screening for identifying early stages of the cohort. Using the A30P mouse model of PD, the authors monitored not only functional (behavioral and physiological) histopathological but also molecular changes in the ENS (several parameters including behavioral and physiological functions (gastrointestinal contractions)), and histopathological changes in order to identify biomarkers in the gut related to early stages of PD [ 68 ]. In this mouse model, they were able to identify a whole panel of intestinal biomarkers of early PD, including miRNAs regulating α-Syn properties.…”

“…Therefore, the results should also be confirmed in GIT tissues in patients in the early pre-motor stages of the disease. Collectively these data suggest a good potential for minimally invasive GIT biopsy and miRNA screening as one of the diagnostic methods for early detection of PD [ 68 ].…”

“…MicroRNAs (miRNAs) are endogenous single-stranded noncoding RNAs consisting of 17–24 base-pairs that function as important post-transcriptional regulators of gene expression. Furthermore, miRNAs have emerged as suitable tools for the diagnosis, prognosis, and even as targets for new therapeutical strategies for a variety of pathologies [ 67 , 68 ]. In this regard, miRNAs are also involved in the regulation of α-Syn, with several miRNAs identified that target α-Syn through direct interaction, or that contribute to changes in α-Syn levels and toxicity indirectly, involving various pathways regulating α-Syn clearance.…”

The Diagnostic Potential of Amyloidogenic Proteins

“…For example, aggregated forms of α-syn have been found in the digestive system of PD patients [ 179 ]. The diagnostic relevance of this finding is twofold: it shows that other parts of the body can be examined for potential biomarkers of neurodegeneration [ 180 ]; it also implies that patients may show symptoms/disorders that are apparently unrelated with the neurodegenerative condition but instead could be used for early diagnosis.…”