Parkinson mice show functional and molecular changes in the gut long before motoric disease onset

• DOI: 10.1186/s13024-021-00439-2
• Publication Date: 2021-06-02T09:04:59Z
• Authors: Manuela Gries; Anne Christmann; Steven Schulte; Maximilian Weyland; Stephanie Rommel; Monika Martin; Marko Baller; Ralph Röth; Stefanie Schmitte...; Marcus Unger; Yang Liu; Frederik Sommer; Timo Mühlhaus; Michael Schroda; Jean-Pierre Timme...; Isabel Pintelon; Gudrun A. Rappold; Markus Britschgi; Hilal Lashuel; Michael D. Menger; Matthias W. Laschke; Beate Niesler; Karl-Herbert Schäfer
• Keywords: Protein-and miRNA biomarkers ; Mice, Inbred C57BL [MeSH] ; Parkinsonian Disorders/physiopathology [MeSH] ; Enteric Nervous System/physiopathology [MeSH] ; Gastrointestinal Motility/physiology [MeSH] ; Animals [MeSH] ; Prodromal Symptoms [MeSH] ; Gastrointestinal Diseases/etiology [MeSH] ; Mice [MeSH] ; Gastrointestinal Diseases/physiopathology [MeSH] ; Gastrointestinal motility ; Early onset ; Research Article ; Enteric nervous system ; Parkinson’s disease; Gastrointestinal Diseases; Protein-and miRNA biomarkers; alpha-synuclein; early onset; Prodromal Symptoms; 610; gastrointestinal motility; Enteric Nervous System; lipid-peroxidation; Mice; enteric nervous system; subcellular-localization; Parkinsonian Disorders; enteric nervous-system; oxidative stress; Animals; alzheimers-disease; RC346-429; wild-type; ddc:610; Gastrointestinal motility; RC952-954.6; protein-and mirna biomarkers; 3. Good health; Mice, Inbred C57BL; Geriatrics; substantia-nigra; parkinson's disease; Parkinson’s disease; Human medicine; Neurology. Diseases of the nervous system; Enteric nervous system; Gastrointestinal Motility; binding protein calretinin; Early onset; myenteric plexus; Research Article

Abstract Background There is increasing evidence that Parkinson’s disease (PD) might start in the gut, thus involving and compromising also the enteric nervous system (ENS). At the clinical onset of the disease the majority of dopaminergic neurons in the midbrain is already destroyed, so that the lack of early biomarkers for the disease represents a major challenge for developing timely treatment interventions. Here, we use a transgenic A30P-α-synuclein-overexpressing PD mouse model to identify appropriate candidate markers in the gut before hallmark symptoms begin to manifest.

Methods Based on a gait analysis and striatal dopamine levels, we defined 2-month-old A30P mice as pre-symptomatic (psA30P), since they are not showing any motoric impairments of the skeletal neuromuscular system and no reduced dopamine levels, but an intestinal α-synuclein pathology. Mice at this particular age were further used to analyze functional and molecular alterations in both, the gastrointestinal tract and the ENS, to identify early pathological changes. We examined the gastrointestinal motility, the molecular composition of the ENS, as well as the expression of regulating miRNAs. Moreover, we applied A30P-α-synuclein challenges in vitro to simulate PD in the ENS.

Results A retarded gut motility and early molecular dysregulations were found in the myenteric plexus of psA30P mice. We found that i.e. neurofilament light chain, vesicle-associated membrane protein 2 and calbindin 2, together with the miRNAs that regulate them, are significantly altered in the psA30P, thus representing potential biomarkers for early PD. Many of the dysregulated miRNAs found in the psA30P mice are reported to be changed in PD patients as well, either in blood, cerebrospinal fluid or brain tissue. Interestingly, the in vitro approaches delivered similar changes in the ENS cultures as seen in the transgenic animals, thus confirming the data from the mouse model.

Conclusions These findings provide an interesting and novel approach for the identification of appropriate biomarkers in men.