"Using a combined approach of Drosophila genetics and in vitro cell culture experiments, we aim to better understand the basic biological function of genes associated with late-onset Alzheimer’s disease and familial frontotemporal dementia, determining how these genes contribute to dysfunction of neurons and glial in these disorders." Owen Peters
UK DRI Momentum Award
Dr Owen Peters joined the UK DRI at Cardiff in 2018, where he has established his first group. He originally obtained his PhD from Cardiff University, using rodent models to study the role of synuclein proteins in neuronal function and dysfunction. He went on to complete postdoctoral training in the US, where he characterised a novel mouse model of C9ORF72, crucial in Amyotrophic Lateral Sclerosis and Frontotemporal dementia research, before focusing on drosophila. In this Momemtum Award at the UK DRI at Cardiff, his lab will use drosophila to investigate genetics of neurodegeneration.
1. At a glance
Using genetics to understand the causes neurodegenerative disease
Neurodegenerative diseases including Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) all involve the gradual loss of function and death of neurons. Although each disease affects different parts of the nervous system and causes different symptoms, they are all thought to involve disturbances to waste disposal system in neurons that leads to a build-up of toxic proteins.
Exploring the common biological mechanisms that contribute to the development of different neurodegenerative diseases will offer vital clues that could lead to new treatments. Using powerful new approaches that involve examining the DNA sequences of thousands of people, researchers have now identified several genetic variations that can influence the risk of getting late-onset AD. Additionally, although ALS and FTD are distinct diseases, they have extensive overlaps – and scientists have recently discovered that some rare inherited forms can even be caused by faults within the same genes.
Dr Owen Peters is using cutting-edge experimental approaches to understand the role of genes linked with AD, ALS and FTD in maintaining the health of neurons and other brain cells – often utilising the fruit fly as a research model. He is particularly focussing on the waste disposal system in neurons to identify new genetic factors that can impact on its function and may contribute to dementia and other forms of neurodegeneration.
2. Scientific goals
Genome-wide association studies (GWAS) have identified genetic variances associated with increased risk of developing late-onset Alzheimer’s disease (AD), however, the precise contribution of these to pathogenesis is unknown. It is often unclear what effect the genetic variance has upon expression of their surrounding genes and in which cells these changes manifest in the mature brain.
Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal dementia (FTD) can be caused by mutations within the same genes. How mutations in genes including C9ORF72 and TBK1 drive both neurodegenerative phenotypes is currently unclear and compounded by the partial understanding of the function of these genes in the central nervous system.
The endolysosomal and autophagy machinery play a critical role in maintaining healthy cells, clearing excess and dysfunctional intracellular molecules through a tightly-regulated process. Disruption of both systems is widely reported in neurodegenerative disease including AD and FTD. Though many components are common to all cells, precisely how these processes are organised and regulated by specific cell types and at different stages in development is only partially understood. The longevity, large volume and highly compartmentalised morphology of neurons, consisting of the cell body, axon, dendrites and synapses, suggests specific mechanisms must have evolved to determine where and when the endolysosomal and autophagy machinery can function.
The team are using a combination of cell culture and Drosophila-based approaches to study the underlying biology of genes associated with neurodegenerative disease.
Main objectives and research goals:
1. To understand the role of genes associated with increased risk of Alzheimer’s disease in maintaining a healthy central nervous system. Assessing how changes in the expression of AD risk-genes affects the function and cellular health of neurons and glia in ageing brains of Drosophila.
2. To determine how mature neurons regulate and organise the endolysosomal and autophagy machinery. Conducting an unbiased genetic screen to identify novel factors regulating the number, location and function of autophagic vesicles within the neurons of adult Drosophila, following up on genes of interest in mammalian and human neuron model systems.
3. To study the role of hereditary mutant genes in the pathogenesis of Amyotrophic lateral sclerosis/Frontotemporal dementia (ALS/FTD). Using high-throughput image analysis of human cell culture systems to assess novel functions for some of these genes in neurons and glia.
3. Team members
Dr Bilal Malik (Postdoctoral Researcher)
Leonardo Amadio (Research Technician)
Eilish MacKinnon (PhD student)
Andrew Lloyd (PhD Student)
Louise Townsend (PhD Student)
4. Collaborations
Within UK DRI:
- Dr Gaynor Smith, UK DRI at Cardiff
Beyond UK DRI:
- PerkinElmer
5. Topics
Drosophila, Alzheimer’s disease, Frontotemporal dementia, risk genes, endolysosomal system, autophagy
6. Techniques
Confocal microscopy, Drosophila genetic screening, high-throughput image analysis
7. Key publications
Peters, O. M.et al. 2018. Loss of Sarm1 does not suppress motor neuron degeneration in the SOD1G93A mouse model of amyotrophic lateral sclerosis. Human Molecular Genetics 27(21), pp. 3761-3771.
Peters, O. M.et al. 2015. Human C9ORF72 hexanucleotide expansion reproduces RNA foci and dipeptide repeat proteins but not neurodegeneration in BAC transgenic mice. Neuron 88(5), pp. 902-909.
Peters, O. M., Ghasemi, M. and Brown, R. H. 2015. Emerging mechanisms of molecular pathology in ALS. The Journal of Clinical Investigation 125(5), pp. 1767-1779.
Peters, O. M.et al. 2015. Gamma-synuclein pathology in amyotrophic lateral sclerosis. Annals of Clinical and Translational Neurology 2(1), pp. 29-37.
Peters, O. M.et al. 2013. Chronic administration of dimebon does not ameliorate amyloid-β pathology in 5xFAD transgenic mice. Journal of Alzheimer's Disease 36(3), pp. 589-596.
Peters, O. M.et al. 2013. Chronic administration of dimebon ameliorates pathology in Tau P301S transgenic mice. Journal of Alzheimer's Disease 33(4), pp. 1041-1049.
