Salker, M. | bioRxiv Science

bioRxiv2021

Marker-free imaging of α-Synuclein aggregates in a rat model of Parkinson' disease using Raman microspectroscopy

A hallmark of Parkinsons disease (PD) is the formation of Lewy bodies in the brain. Lewy bodies are rich in the aggregated form of misfolded -Synuclein (-Syn). The brain from PD patients can only be analysed after post-mortem, limiting the diagnosis of PD to the manifestation of motor symptoms. In PD patients and animal models phosphorylated -Syn was detected in the gut, thus, raising the hypothesizes that early-stage PD could be diagnosed based on colon tissues biopsies. Non-invasive marker-free technologies represent an ideal method to potentially detect aggregated -Syn in vivo. Raman microspectroscopy has been established for the detection of molecular changes such as alterations of protein structures. Here, the olfactory bulb in the brain and the muscularis mucosae of colon tissue sections of a human BAC-SNCA transgenic (TG) rat model was analysed using Raman imaging and microspectroscopy. Raman images from TG and WT rats were investigated using spectral, principal component and true component analysis. Spectral components indicated protein aggregates (spheroidal oligomers) in TG rat brain and colon tissues even at a young age but not in WT. In summary, we have demonstrated that Raman imaging is capable to detect -Syn aggregates in colon tissues of a PD rat model and making it a promising tool for future use in PD pathology.

neuroscience↗

bioRxiv2020

Overexpression of human alpha-synuclein leads to dysregulated microbiome and metabolites with ageing in a rat model of Parkinson disease

Since Braaks hypothesis stating that sporadic Parkinsons disease follows a specific progression of the pathology from the peripheral to the central nervous system and can be monitored by detecting accumulation of the alpha-Synuclein protein. There is growing interest in understanding how the gut (commensal) microbiome can regulate alpha-Synuclein accumulation which can lead to PD. We studied a transgenic rat model overexpressing the human alpha-Synuclein and found that the protein overexpression resulted in gut alpha-Synuclein expression and aggregation in the gut neurons with advancing age. A progressive gut microbial composition alteration characterized by the reduction of Firmicutes to Bacteroidetes ratio could be detected in the young transgenic rat model and interestingly this ratio was then increased with aging. This observation was accompanied in older animals by intestinal inflammation, increase gut permeability and a robust alteration in metabolites production characterized by the increase of succinate level in the feces and serum. Manipulation of the gut bacteria by short-term antibiotics treatment revealed a complete loss of short-chain fatty acids (SCFAs) and reduction in succinate levels. Although antibiotics treatment did not change alpha-synuclein expression in the enteric nervous system of the colon, it can reduce alpha-synuclein expression in the olfactory bulb of the transgenic rats. In summary, synchronous with ageing, our data emphasize that the gut microbiome dysbiosis leads to a specific alteration of gut metabolites which are reflected in the serum and can be modulated by the environment.

neuroscience↗