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Published on: May 2, 2018
Mechanisms of molecular mimicry involving the microbiota in neurodegeneration
1Department of Neurology, University of Louisville School of Medicine, Louisville, KY, USA.
Abstract:
The concept of molecular mimicry was established to explain commonalities of structure which developed in response to evolutionary pressures. Most examples of molecular mimicry in medicine have involved homologies of primary protein structure which cause disease. Molecular mimicry can be expanded beyond amino acid sequence to include microRNA and proteomic effects which are either pathogenic or salutogenic (beneficial) in regard to Parkinson's disease, Alzheimer's disease, and related disorders. Viruses of animal or plant origin may mimic nucleotide sequences of microRNAs and influence protein expression. Both Parkinson's and Alzheimer's diseases involve the formation of transmissible self-propagating prion-like proteins. However, the initiating factors responsible for creation of these misfolded nucleating factors are unknown. Amyloid patterns of protein folding are highly conserved through evolution and are widely distributed in the world. Similarities of tertiary protein structure may be involved in the creation of these prion-like agents through molecular mimicry. Cross-seeding of amyloid misfolding, altered proteostasis, and oxidative stress may be induced by amyloid proteins residing in bacteria in our microbiota in the gut and in the diet. Pathways of molecular mimicry induced processes induced by bacterial amyloid in neurodegeneration may involve TLR 2/1, CD14, and NFκB, among others. Furthermore, priming of the innate immune system by the microbiota may enhance the inflammatory response to cerebral amyloids (such as amyloid-β and α-synuclein). This paper describes the specific molecular pathways of these cross-seeding and neuroinflammatory processes. Evolutionary conservation of proteins provides the opportunity for conserved sequences and structures to influence neurological disease through molecular mimicry.
Insights
Molecular mimicry, involving protein structure and microRNAs, may explain neurodegenerative diseases like Parkinson's and Alzheimer's. Bacterial amyloids in the gut can trigger these processes, impacting brain health.
Area of Science:
- Neuroscience
- Evolutionary Biology
- Immunology
Background:
- Molecular mimicry, initially defined by protein sequence homology, explains diseases.
- This concept extends to microRNA and proteomic effects, influencing neurodegenerative disorders.
- Parkinson's and Alzheimer's diseases feature prion-like proteins, but their origins remain unclear.
Purpose of the Study:
- To expand the concept of molecular mimicry beyond protein sequences.
- To explore the role of molecular mimicry in Parkinson's and Alzheimer's diseases.
- To elucidate the pathways linking microbial amyloids to neuroinflammation and neurodegeneration.
Main Methods:
- Comparative analysis of protein structures and microRNA sequences.
- Investigation of viral mimicry of nucleotide sequences.
- Examination of amyloid protein structures and their evolutionary conservation.
- Analysis of molecular pathways involving bacterial amyloids, innate immunity, and neuroinflammation.
Main Results:
- Molecular mimicry extends to microRNAs and proteomic effects, impacting neurodegeneration.
- Viruses can mimic microRNA sequences, affecting protein expression.
- Bacterial amyloids from diet and microbiota may induce cross-seeding of misfolding, alter proteostasis, and cause oxidative stress.
- Pathways involving TLR 2/1, CD14, and NFκB mediate bacterial amyloid-induced neuroinflammation.
- Microbiota priming of the innate immune system can exacerbate responses to cerebral amyloids like amyloid-beta and alpha-synuclein.
Conclusions:
- Molecular mimicry is a significant factor in neurodegenerative diseases, extending beyond protein sequence homologies.
- Bacterial amyloids and conserved protein structures play a crucial role in initiating and propagating neuroinflammatory and neurodegenerative processes.
- Understanding these pathways offers potential therapeutic targets for Parkinson's, Alzheimer's, and related disorders.
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