Interactions between pathological and functional amyloid: A match made in Heaven or Hell?

Area of Science:

• Biochemistry
• Microbiology
• Neuroscience

Background:

• Amyloid proteins exist in pathological (neurodegenerative diseases) and functional (bacterial biofilms) forms.
• The human body hosts pathological human amyloid (PaHA), functional bacterial amyloid (FuBA) from the microbiome, and dietary amyloid.
• Amyloid fragments can propagate pathological forms and cross-seed dissimilar sequences, with FuBA-PaHA interactions increasingly implicated in vivo.

Purpose of the Study:

• To understand the structural and bioinformatic basis of cross-talk between FuBA and PaHA.
• To investigate the mechanisms of FuBA-PaHA interactions, including cross-stimulation and inhibition.
• To explore the role of these interactions in the transmission and development of neurodegenerative diseases.

Main Methods:

• Utilized atomic-level structures of bacterial amyloids CsgA and FapC.
• Performed in vitro and in vivo experiments to study FuBA-PaHA interactions.
• Employed computational methods to analyze sequence and structure relationships and chaperone activity.

Main Results:

• Uncovered significant cross-stimulation and inhibition between FuBA and PaHA, despite limited sequence homology.
• Demonstrated that FuBA and PaHA can interact via the gut-brain axis, influencing aggregation and inflammation.
• Showed that microbiome chaperones can recognize and inhibit both FuBA and PaHA growth.

Conclusions:

• Heterotypic interactions between FuBA and PaHA are a vital aspect of the amyloid phenomenon.
• These interactions have significant implications for neurodegenerative disease development and transmission.
• Further research into FuBA-PaHA interactions offers a vibrant frontier for understanding and treating amyloid-related conditions.