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

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.

Probiotics synergized with conventional regimen in managing Parkinson’s disease

“…Patients with PD are characterized by classic motor symptoms, such as resting tremor, bradykinesia, and rigidity, as well as gastrointestinal (GI) symptoms, including constipation, slower colonic transit time, and small intestinal bacterial overgrowth 2 . Notably, the GI symptoms of PD patients often precede the motor signs, suggesting an association between gut abnormalities and the onset of PD 3 .…”

RNA-based stable isotope probing provides no indication for rapid α-synuclein assimilation by murine gut bacteria

“…In case of any 13 C assimilation into RNA, we would have expected to see shifts of the distribution curves towards higher densities, particularly for the 4 and 24 h incubations with 13 C synuclein. However, there was no difference in RNA distribution between both control incubations (0 h) and 12 C and the 13 C incubations. In fact, all distribution curves were nearly identical.…”

“…(b) Density-dependent distribution of RNA. RNA was extracted from murine gut contents, incubated with 12 C α-synuclein and 13 C α-synuclein for 0, 4 and 24 h, respectively, and separated by ultracentrifugation using a CsTFA density gradient. RNA concentration is given as relative RNA content, whereby the highest RNA concentration of each gradient is set as 100 % (543.50 ng ml −1 0 h 12 C, 487.98 ng ml −1 0 h 13 C, 497.92 ng ml −1 4 12 C, 424.94 ng ml −1 4 h 13 C, 326.45 ng ml −1 24 h 12 C, 365.21 ng ml −1 24 h 13 C).…”

“…In addition to other α-synucleopathies, PD in particular has been reported to come with increased expression of α-synuclein in the enteric nervous system [8][9][10], suggesting that the synucleinopathy arises first in the gastrointestinal tract (GIT) and then spreads to the central nervous system of the brain at a later stage of the disease [11]. A recent study in a PD mouse model demonstrated alterations in both ENS composition and gut motility at very early timepoints, while the brain did not yet show significant changes [12]. Paillusson et al reported that enteric neurons are physiologically secreting α-synuclein [13], which could potentially make it reachable for gut bacteria and serve as a seed for further propagation.…”

Modeling Parkinson's disease‐related symptoms in alpha‐synuclein overexpressing mice

“…Similar to olfactory deficits, gastrointestinal dysfunction can occur in PD patients as early as 20 years before the development of motor symptoms (Poewe, 2008 ; Savica et al., 2009 ). Gastrointestinal dysfunction is likely caused by α‐syn pathology in the autonomic nervous system and in brain areas controlling autonomic nervous system input, including the dorsal motor nucleus of vagus, enteric nervous system, adrenal medulla, and sympathetic ganglia (Boeve et al., 2007 ; Braak et al., 2006 ; Gries et al., 2021 ; Jellinger, 2015 ).…”