Host - Microbe interactions in Parkinson's using a Caenorhabditis elegans (C. elegans)- Escherichia coli (E. coli) Holobiont Model
Lead Research Organisation:
University of Cambridge
Department Name: Chemistry
Abstract
PhD project strategic theme: Bioscience for an integrated understanding of health
Parkinson's disease (PD) is a progressive neurological disorder that manifest itself through its gradual degenerative effects on the motor system of the nervous system. This clinical manifestation is pathologically derived from the abnormal accumulation and misfolding of a- Synuclein (aS), forming neurotoxic insoluble amyloid fibrils in Lewy bodies. This leads to the degradation of dopamine producing neurons in the substantia nigra of the brain. Resulting in the development of the still incurable and second most prevalent neurodegenerative disease, PD which is more prevalent amongst the ageing population, of above 65 years of age.
Recent research provides evidence that signals peripheral to the central nervous system, particularly from the gastrointestinal tract and gut microbiota, are involved in the progression of PD. For example, aS pathology begins in peripheral tissues such as in the intestines and gradually spreads to multiple brain regions.
The human gastrointestinal tract encompasses the densest microbial symbiotic ecosystem within the body. Altogether, these microbes which primarily constitute of bacteria produces over a 100 times more protein-coding genes than the human genome. Recently, cumulative evidence suggests that microbes harbored in the gastrointestinal tract are fundamental to the development and health of their host. For they aid in vitamin biosynthesis, improved energy and nutrient uptake through various metabolic pathways, and alleviate intestinal pathogen infections by helping develop and maturate the immune system providing a competitive environment for resources. The gut microbiota has also been shown to impact brain function by producing metabolites that enter the bloodstream. However, how gut bacteria affect aS aggregation is still unclear.
To investigate the effect of microbiota in PD, we will use, Caenorhabditis elegans (C. elegans) as a model to demonstrate aS aggregation. C. elegans is an ideal model because its gut microbiota can be precisely controlled to study physiological processes at both the single-species and single-gene levels, and C. elegans has been validated as a valuable model of studying molecular mechanisms of Parkinson's disease and protein aggregation.
Using a well-established C. elegans model of PD that expresses human aS in muscle cells. Phenotypic assays will be employed through the application of the E. coli KEIO Knockout Collection for all nonessential genes and the Phenomic Microarrays technology (Biolog), to respectively reveal the effects of bacterial genetic impairment and nutritional supplementation on the physiology of aS worms. Then, to further unravel the mechanisms underlying these interactions in the context of aS aggregation in the worms, RNA Sequencing, metabolomics, fluorescence recovery after photobleaching (FRAP), atomic force microscopy (AFM) and many more techniques will be employed for biological and biophysical characterisation of aS aggregation.
Ultimately, host - microbe interactions in the context of aS could help to elucidate the processes involved in the protein aggregation associated in PD.
Parkinson's disease (PD) is a progressive neurological disorder that manifest itself through its gradual degenerative effects on the motor system of the nervous system. This clinical manifestation is pathologically derived from the abnormal accumulation and misfolding of a- Synuclein (aS), forming neurotoxic insoluble amyloid fibrils in Lewy bodies. This leads to the degradation of dopamine producing neurons in the substantia nigra of the brain. Resulting in the development of the still incurable and second most prevalent neurodegenerative disease, PD which is more prevalent amongst the ageing population, of above 65 years of age.
Recent research provides evidence that signals peripheral to the central nervous system, particularly from the gastrointestinal tract and gut microbiota, are involved in the progression of PD. For example, aS pathology begins in peripheral tissues such as in the intestines and gradually spreads to multiple brain regions.
The human gastrointestinal tract encompasses the densest microbial symbiotic ecosystem within the body. Altogether, these microbes which primarily constitute of bacteria produces over a 100 times more protein-coding genes than the human genome. Recently, cumulative evidence suggests that microbes harbored in the gastrointestinal tract are fundamental to the development and health of their host. For they aid in vitamin biosynthesis, improved energy and nutrient uptake through various metabolic pathways, and alleviate intestinal pathogen infections by helping develop and maturate the immune system providing a competitive environment for resources. The gut microbiota has also been shown to impact brain function by producing metabolites that enter the bloodstream. However, how gut bacteria affect aS aggregation is still unclear.
To investigate the effect of microbiota in PD, we will use, Caenorhabditis elegans (C. elegans) as a model to demonstrate aS aggregation. C. elegans is an ideal model because its gut microbiota can be precisely controlled to study physiological processes at both the single-species and single-gene levels, and C. elegans has been validated as a valuable model of studying molecular mechanisms of Parkinson's disease and protein aggregation.
Using a well-established C. elegans model of PD that expresses human aS in muscle cells. Phenotypic assays will be employed through the application of the E. coli KEIO Knockout Collection for all nonessential genes and the Phenomic Microarrays technology (Biolog), to respectively reveal the effects of bacterial genetic impairment and nutritional supplementation on the physiology of aS worms. Then, to further unravel the mechanisms underlying these interactions in the context of aS aggregation in the worms, RNA Sequencing, metabolomics, fluorescence recovery after photobleaching (FRAP), atomic force microscopy (AFM) and many more techniques will be employed for biological and biophysical characterisation of aS aggregation.
Ultimately, host - microbe interactions in the context of aS could help to elucidate the processes involved in the protein aggregation associated in PD.
Organisations
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| BB/M011194/1 | 01/10/2015 | 31/03/2024 | |||
| 2274374 | Studentship | BB/M011194/1 | 01/10/2019 | 29/02/2024 | Samuel Dada |