The Influence of Bacterial Amyloid on Alpha-synuclein Misfolding in a Pre-clinical Model

Objective/Rationale:             
In Parkinson’s disease (PD), in nerve cells in the brain and in the intestine, alpha-synuclein proteins are misformed with abnormal folds and develop small toxic fibers.  The reason why alpha-synuclein becomes misfolded in the brain or the gut is unknown. We hypothesize that alpha-synuclein misfolding in gut and brain neurons in caused by exposure to proteins of similar structure that are contained in bacteria that reside in the mouth and gut.

Project Description:             
Abnormal folding of alpha-synuclein has been described in aged pre-clinical models. We will establish three groups of middle-aged pre-clinical models, and expose them orally to bacteria that have amyloid proteins, which have a similar structure to misfolded alpha-synuclein. We will study the pre-clinical models for nine months as they age and develop stable colonies in the mouth and gut with amyloid-containing bacteria. Control bacteria that do not have the amyloid protein will also be used. We will evaluate the effects of oral administration of the amyloid-producing bacteria on growth of the bacteria in the gut, oral infections, markers in the blood for inflammation and free radicals, and development of misfolded alpha-synuclein in gut and brain neurons.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:                     
If our hypothesis is correct, it may be possible to alter PD risk and/or treat the disease by altering exposure in the intestine to amyloid-containing bacteria. This might be done through diet, prebiotics (which alter the growth of bacteria in the intestine by providing food for the bacteria) or probiotics (which directly supply desired bacteria to the intestine). 

Anticipated Outcome:          
We will learn if exposure to amyloid-containing bacteria in the mouth and gut influence the development of misfolded alpha-synuclein in the brain and intestine of pre-clinical models. We will also learn how the bacteria influence the process of protein misfolding.  This will point to the importance of the bacteria residing in our intestines for human health and disease. The results will be valuable for development of preventive and therapeutic strategies.