Dr Owen Peters

Lecturer in Dementia Research

School of Biosciences

Email:
petersom@cardiff.ac.uk
Location:
Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ

Research overview

Understanding the role of neurodegenerative disease risk genes in the ageing nervous system

Though many common neurodegenerative diseases exist in hereditary forms, the vast majority of cases occur sporadically. Human genetic studies have identified many polymorphisms associated with increased risk of developing disorders such as Alzheimer’s disease, but it is frequently unclear how these mutations contribute to pathogenesis.

My laboratory uses a combination of invertebrate, mammalian and cellular model systems to understand how genes associated with increased risk for neurodegenerative diseases contribute to maintenance of the ageing nervous system, focusing on Alzheimer’s disease, frontotemporal dementia and motor neuron diseases. We are additionally testing how ageing neurons organised and regulate their endo-lysosomal and autophagy machinery, using the power of fly genetics to identify novel, neuron-specific regulatory genes for these systems.

Research goals

1. Understand the role of genes associated with increased risk of Alzheimer’s disease in maintaining a healthy central nervous system.

2. Determine how mature neurons regulate and organise the endo-lyosomal and autophagy machinery.

3. To study the role of hereditary mutant genes in the pathogenesis of Amyotrophic Lateral Sclerosis/Frontotemporal Dementia (ALS/FTD).

Throughout my research career I have been driven to further our understanding of the molecular processes contributing towards neurodegenerative disease. I conducted my PhD training in the laboratory of Prof Vladimir Buchman in Cardiff University, using rodent models to understand the role of synuclein proteins to neurodegeneration and basic neuronal function. Wishing to work in an academic environment with a focus on basic neuroscience as well as neurodegenerative disease and therapeutics, I moved to a collaborative post-doctoral research position between the laboratories of Dr Marc Freeman and Dr Robert H. Brown in the University of Massachusetts Medical School, USA. During my studies in UMMS I characterized a novel mouse model of the Amyotrophic Lateral Sclerosis/Frontotemporal Dementia gene C9ORF72, and assessed the role of an evolutionarily conserved mechanism of programmed axon destruction in rodent models of neurodegenerative diseases ALS and Parkinson’s disease. In 2016 I moved with the Freeman lab to Oregon Health and Sciences University, USA to focus on training in the use of powerful genetic and imaging techniques in the fruitfly Drosophila melanogaster for use in studying aspects of neuronal biology that contribute to neurodegenerative disease.

My current research uses a combination of invertebrate, mammalian and cellular model systems to understand how genes associated with increased risk for neurodegenerative diseases contribute to maintenance of ageing neurons and glia, with a focus on Alzheimer’s disease, frontotemporal dementia and motor neuron diseases. We are additionally working to understand how ageing neurons regulate the endo-lysosomal and autophagy machinery, using the power of fly genetics to identify novel, neuron-specific regulatory genes for these systems.

Understand the role of genes associated with increased risk of Alzheimer’s disease in maintaining a healthy central nervous system

Genome-wide human studies 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 (increase/decrease in expression) and in which cells these changes manifest in the mature brain. In vivo testing in model organisms is a robust means of assessing how changes in candidate risk gene expression may affect the ageing brain and susceptibility to AD-like pathology. The fruitfly Drosophila melanogaster presents a powerful tool in which to study the function of conserved AD risk genes in a genetically tractable in vivo model system. Flies have a small, well-defined brain that contains a large repertoire of neuronal and glial subtypes, ideal for testing the role of risk genes in differing cell types. Their genome is readily modified, with a large toolbox of techniques available for mutating and altering gene expression.

In collaboration with the laboratory of Dr Gaynor Smith and members of the Dementia Research Institute (DRI) we will assess how changes in expression of AD risk-genes affects the brains of adult Drosophila. We will use cutting-edge genetics to test a spectrum of phenotypes including cellular morphology, functional and behavioural outcomes.

Determine how mature neurons regulate and organise the endo-lyosomal and autophagy machinery

The endo-lysosomal and autophagy machinery play a critical role in maintaining healthy cells, clearing excess and dysfunctional intracellular molecules through a tightly regulated process. Though many components of the endo-lysosome and autophagy machinery are common to all cells, precisely how these processes are organized and regulated by specific cell types and at different stages in development is only partially understood. The longevity, large volume and highly compartmentalized morphology of neurons, consisting of cell body, axon, dendrites and synapses, suggests specific mechanisms must have evolved to determine where and when the endo-lysosomal and autophagy machinery can function.

Utilizing state-of-the-art microscopy and clonal neuronal labeling, we will use unbiased genetic screening approaches to identify novel factors regulating the number, location and function of endo-lysosomal and autophagic vesicles within in the neurons of adult Drosophila. Where appropriate, the evolutionary conservation of our findings from flies will then be tested using mammalian and human neuron model systems.

To study the role of hereditary mutant genes in the pathogenesis of Amyotrophic Lateral Sclerosis/Frontotemporal Dementia (ALS/FTD)

Though presenting diverse clinical symptoms, the motor neuron disease Amyotrophic Lateral Sclerosis (ALS) and Fronto-Temporal Dementia (FTD) can be caused by mutations within the same genes. How mutations in genes including C9ORF72 and TBK1 drive both neurodegenerative phenotypes is unclear and compounded by our partial understanding of the function of these genes in the central nervous system. We are utilizing in vivo fly models and human cell culture systems to assess novel functions for some of these genes in neurons and glia, aiming to identify means of therapeutic intervention in the devastating neurodegenerative diseases with which they are associated.

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