Parkinson’s disease (PD) is a neurological disorder caused by the degeneration of nerve cells. This results from the aggregation of a misfolded protein called alpha-synuclein (AS) in the hippocampal region of the brain. The existent theory suggests that alpha-synuclein aggregation causes the loss of motor functions in PD patients. However, very little is known about the initiation of this protein aggregation.

A recent report published in Scientific Reports suggests that an amyloid protein from a gut bacteria might be initiating the protein aggregation in PD. The study conducted in two models – rats and nematodes (C. elegans) – revealed intriguing results. Rats and C. elegans exposed to E. coli producing an amyloid protein curli showed increased deposition of AS in the gut and the brain when compared to those that were exposed to mutant bacteria unable to synthesize curli.

Common bacterium Escherichia coli makes and employs amyloid fibers, the same types of fibers that are the calling cards of many neurodegenerative diseases. @www.medgadget.com

Results indicate that these organisms showed increased deposition of misfolded AS in the gut and the brain when exposed to E. coli producing the protein curli when compared to the unexposed organisms. Curli is the best studied bacterial amyloid protein secreted by E. coli and its key element, CsgA, has been found to contain amyloidogenic peptide repeat motifs that have a consensus with the yeast and human prions and AS. Due to these similarities, the group hypothesized that amyloid proteins made by the commensal partners function to trigger misfolding of amyloid proteins such as AS through cross-seeding, and prime the innate immune system thereby enhancing inflammatory responses to AS. This hypothesis was validated by exposing aged Fischer rats and transgenic C. elegans expressing human AS to bacteria producing curli. The control group consisted of animals that were exposed to mutant bacteria lacking the operons required for curli synthesis. The group assessed the accumulation and aggregation of AS and the inflammation using immunocytochemistry and other molecular techniques. The animals were exposed to the agent through the oral route of administration. The rats exposed to wild-type bacteria producing curli displayed enhanced AS deposition in the myenteric plexus, the submucosa, and in neurons in the hippocampus and striatum, when compared to the control group exposed to mutant bacteria that lacked the capacity to produce curli. AS deposits in the gut did not aggregate, but the AS depositions in the neurons formed aggregates.

In the nematode study, a transgenic C. elegans line expressing human AS fused with YFP (AS-YFP) in body wall muscle was used. This facilitated the visualization of aggregated AS-YFP in live animals usin g fluorescence microscopy. These C. elegans fed with curli-producing E. coli showed increased AS deposits when compared to those fed with the mutant E. coli lacking curli synthesis. AS-aggregates were seen to be accumulated in the head first and then moved to the tail during adulthood. Cytosolic and mitochondrial oxidative stress markers were downregulated indicating that the protein deposition is independent of oxidative stress. Results from swimming tests showed a decreasing trend with 15-20% decreased thrashing rate in worms exposed to wild-type curli-producing E. coli when compared to the mutants.

Also, the exposed organisms showed immune response to the bacterial protein was identical to that found in PD towards AS. Since the immune response on recognition of this bacterial amyloid protein and that of AS and AB comprise of common pathways involving TLR 2/1, NLRP3, CD14, NFkB and iNOS, it was hypothesized that exposure to bacterial amyloid had caused the priming of immune cells to create enhanced immune responses in the brain of exposed animals. For this reason, the researchers studied the expression of markers associated with neuroinflammation, including microgliosis, astrogliosis, and the pro-inflammatory cytokines including IL-6, IL-1, TNF and TLR2. Results showed that microgliosis and astrogliosis in the striatum, hippocampus and neocortex was significantly higher in animals exposed to curli-producing bacteria as compared to the two control groups. Similar results were seen for the pro-inflammatory cytokines.

All of these results suggest that the bacterial protein curli must be the triggering agent that initiates AS aggregation by converting the curli protein aggregates into AS aggregates, a phenomenon called cross-seeding. One of the factors that favored this hypothesis was that PD patients have been found to develop digestive problems including constipation and anosmia, and the deposition of aggregated AS in intestinal neurons up to 20 years before diagnosis in PD. Another factors that bridges the gap being the earlier studies suggesting that one bacterial amyloid protein could cause another to adopt a beta sheet structure and the proof that amyloid misfolding could be initiated through exposure in the gut.

http://www.geneticengg.com/wp-content/uploads/2017/02/Curliated-Bug.jpghttp://www.geneticengg.com/wp-content/uploads/2017/02/Curliated-Bug-150x150.jpgJoel JosephGeneticsHealth and Medicinealpha-synuclein,amyloid protein,curli protein,neurobiology,Parkinson's diseaseParkinson’s disease (PD) is a neurological disorder caused by the degeneration of nerve cells. This results from the aggregation of a misfolded protein called alpha-synuclein (AS) in the hippocampal region of the brain. The existent theory suggests that alpha-synuclein aggregation causes the loss of motor functions in PD patients....When Nature and Science meet, Magic happens !