Abstract
Phosphorylated alpha-synuclein (p-α-syn) containing Lewy bodies (LBs) and Lewy neurites (LNs) are neuropathological hallmarks of Parkinson’s disease (PD) in the central nervous system (CNS). Since they have been also demonstrated in the enteric nervous system (ENS) of PD patients, the aim of the study was to analyze enteric p-α-syn positive aggregates and intestinal gene expression. Submucosal rectal biopsies were obtained from patients with PD and controls and processed for dual-label-immunohistochemistry for p-α-syn and PGP 9.5. p-α-syn positive aggregates in nerve fibers and neuronal somata were subjected to a morphometric analysis. mRNA expression of α-syn and dopaminergic, serotonergic, VIP (vaso intestinal peptide) ergic, cholinergic, muscarinergic neurotransmitter systems were investigated using qPCR. Frequency of p-α-syn positive nerve fibers was comparable between PD and controls. Although neuronal p-α-syn positive aggregates were detectable in both groups, total number and area of p-α-syn positive aggregates were increased in PD patients as was the number of small and large sized aggregates. Increased expression of dopamine receptor D1, VIP and serotonin receptor 3A was observed in PD patients, while serotonin receptor 4 and muscarinic receptor 3 (M3R) were downregulated. M3R expression correlated negative with the number of small sized p-α-syn positive aggregates. The findings strengthen the hypothesis that the CNS pathology of increased p-α-syn in PD also applies to the ENS, if elaborated morphometry is applied and give further insights in altered intestinal gene expression in PD. Although the mere presence of p-α-syn positive aggregates in the ENS should not be regarded as a criterion for PD diagnosis, elaborated morphometric analysis of p-α-syn positive aggregates in gastrointestinal biopsies could serve as a suitable tool for in-vivo diagnosis of PD.
Highlights
Parkinson’s disease (PD), a multicentric neurodegenerative disorder that’s progression extends to decades [31], is traditionally characterized by a loss of dopaminergic neurons in the central nervous system (CNS), mainly the brainstem, leading to characteristic cardinal motor symptoms such as bradykinesia, tremor, rigidity, and postural instability [43]
Mean neuronal area was not significant altered (248.2 ± 34.45 μm2) in PD patients compared to controls (282.8 ± 49.65 μm2) (Additional file 1: Figure S2a)
In summary, we provide evidence that suggested in previous studies, the mere presence of p-α-syn positive aggregates in the enteric nervous system (ENS) cannot be regarded as a diagnostic criterion for PD, as p-α-syn is consistently expressed in healthy controls
Summary
Parkinson’s disease (PD), a multicentric neurodegenerative disorder that’s progression extends to decades [31], is traditionally characterized by a loss of dopaminergic neurons in the central nervous system (CNS), mainly the brainstem, leading to characteristic cardinal motor symptoms such as bradykinesia, tremor, rigidity, and postural instability [43]. Impairment of enteric neurotransmission is associated with a wide spectrum of functional GI diseases characterized by severe disturbances of GI motility [38] including constipation [21]. Constipation is one of the leading premotor symptoms in patients with PD arguing for lesions within the ENS accompanying the progression of the disease [49]. Assessment of ENS pathology associated with PD might offer a twofold option: (1) to use the ENS as “diagnostic window into the CNS” [41] possibly allowing early in vivo diagnosis of PD and neuroprotective therapy, (2) to elucidate the pathogenetic mechanisms underlying the high prevalence of GI symptoms, in particular chronic constipation, in patients with PD
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