Age-Dependent Alpha-Synuclein Accumulation and Phosphorylation in the Enteric Nervous System in a Transgenic Mouse Model of Parkinson’s Disease

Abstract

The enteric nervous system (ENS) controls the function of the gastrointestinal tract and has been implicated in various diseases, including Parkinson's disease (PD). PD is a neurodegenerative disease with Lewy bodies (LBs) and Lewy neurites (LNs) as the main pathological features. In addition to the typical motor symptoms in PD, attention has been drawn to non-motor symptoms, such as constipation, implying dysfunction of the ENS. In the present study, we characterized the age-dependent morphological alterations and aggregation of α-synuclein (α-syn), the primary protein component in LBs and LNs, in the ENS in an α-syn transgenic mouse model. We found that the expression and accumulation of α-syn increased gradually in neurons of Meissner's and Auerbach's plexuses of the gastrointestinal tract with age (from 1 week to 2 years). In addition, α-syn was increasingly phosphorylated at the serine 129 residue, reflecting pathological alterations of the protein over time. Furthermore, α-syn was present in different subtypes of neurons expressing vasoactive intestinal polypeptide, neuronal nitric oxide synthase, or calretinin. The results indicated that BAC-α-Syn-GFP transgenic mice provide a unique model in which to study the relationship between ENS and PD pathogenesis.

Post-translational modifications of Parkinson's disease-related proteins: Phosphorylation, SUMOylation and Ubiquitination

“…Recent insights have shown that this protein may also act like a prion, propagating from one neuron to another, therefore enhancing brain degeneration 33,35,36 . Phosphorylation of α-syn at Ser-129 exacerbates the formation of α-syn inclusions, with over 90% of α-syn in LBs being phosphorylated at this residue, resulting in increased toxicity and neuronal death 5,23,27,34 . In a study by Karampetsou and colleagues (2017), α-syn was injected into mouse striatum in its wild type form versus its phosphorylated form, and they observed that phosphorylated α-syn demonstrated enhanced pathology in the SN compared to WT α-syn, increasing dopaminergic neuronal loss 27 .…”

“…In PD it has been shown that all three PTMs play a role in protein aggregation, exocytosis, and degradation 5,[21][22][23]27,[32][33][34] . Therefore, comprehending how these modifications control the function of PD-related proteins, and how these PTMs are altered in disease, could bring new insights into the etiology of the disease, as well as identify potential targets for therapeutic intervention.…”

2D polarization imaging as a low-cost fluorescence method to detect α-synuclein aggregation ex vivo in models of Parkinson’s disease

“…The standard approach to visualize aggregation is to label the proteins of interest with a fluorescence marker, e.g., via immunohistochemical approaches. This way, the presence of bright areas in the fluorescence image suggests accumulation and, therefore, aggregation of the labeled molecules into large agglomerates 6 , 7 , 10 – 13 . This criterion is, however, ambiguous, because it cannot distinguish regions with only high protein expression where proteins are populated without actual aggregation from authentic aggregates containing densely packed protein molecules.…”

Activation of NMDA receptors mediated iron accumulation via modulating iron transporters in Parkinson's disease

“…The main pathologic change of PD is the degeneration of dopamine (DA) neurons in the substantia nigra (SN) pars compacta, resulting in the reduced release of DA in the striatum (Str) (2)(3)(4). Although genetics, environmental factors, oxidative stress, apoptosis, inflammation, and abnormal protein aggregation have been implicated in the pathogenesis of cell death in PD (5)(6)(7)(8), the precise pathogenic mechanisms leading to neurodegeneration of DA neurons in PD are not known. Increasing evidence has proved that elevated nigral iron levels play an important role in the etiology of PD (9)(10)(11)(12)(13).…”