Abstract
BackgroundThere 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.MethodsBased 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.ResultsA 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.ConclusionsThese findings provide an interesting and novel approach for the identification of appropriate biomarkers in men.
Highlights
In Parkinson’s disease (PD), the loss of nigrostriatal dopaminergic neurons causes the hallmark motor symptoms of muscle rigidity, tremor at rest, and bradykinesia [1]
We propose that the enteric nervous system (ENS) of α-synuclein-overexpressing transgenic A30P mice is more sensitive to A30P α-synuclein than the central nervous system (CNS), confirming the assumption, that the A30P mice either belong to the PNS-first PD category or that we do not yet understand that additional triggers might be responsible for the development of one or the other form of PD
To provide evidence that the gut and ENS are involved in PD onset, and to confirm that PD pathogenesis starts in the gut, we investigated whether these functional changes correspond to molecular or morphological abnormalities in the GI tract at this stage
Summary
In Parkinson’s disease (PD), the loss of nigrostriatal dopaminergic neurons causes the hallmark motor symptoms of muscle rigidity, tremor at rest, and bradykinesia [1]. Previous research has shown that the crosstalk between the gut and the brain during PD pathogenesis is mainly influenced by intestinal dysbiosis [13, 14] This suggests that the gastrointestinal (GI) motility deficits associated with PD, such as constipation, are caused by alterations in the microbial composition of the gut, which disrupt gut microbiome and gut-brain-axis may homeostasis and increase inflammation and permeability of the gut [14,15,16,17]. MiRNAs have emerged as important regulators of gene expression, cell differentiation, cell maturation, apoptosis, and immune responses [18] They are present in circulating body fluids [19] as well as gut mucosal tissues, so they can be investigated by colonoscopy [20]. We use a transgenic A30P-αsynuclein-overexpressing PD mouse model to identify appropriate candidate markers in the gut before hallmark symptoms begin to manifest
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