"By using Drosophila genetics to study ageing and neurodegeneration, my lab hopes to better understand mechanisms of dementia through enhanced genetic risk." Gaynor Smith
UK DRI Co-Investigator

Dr Gaynor Smith joins the UK DRI at Cardiff to establish her own research group. Originally studying physiology at Cardiff University, she went on to obtain her PhD in Prof Stephen Dunnett’s lab, researching mitochondrial phenotypes in Parkinson’s disease. Completing postdoctoral training in the USA, Gaynor became specialised in using Drosophila as a model system. Her lab will build on previous work in this Momentum Award, using Drosophila to study genetic risk for neurodegeneration.

1. At a glance

Risky business: Using fruit flies to investigate the genetics of dementia

Alzheimer’s disease (AD) is the most common cause of dementia, with the numbers affected in the UK set to rise in the coming years. Symptoms are wide-ranging but include deteriation of memory caused by the loss of connections between billions of neurons in the brain and eventual cell death.

In the challenge to find treatments for neurodegenerative diseases like AD, scientists require model systems for research investigation as it is often not practical, safe or ethical to test on humans. Fruit flies are an elegant system to explore disease mechanism as they are inexpensive and easy to maintain. Importantly, nearly 75% of human disease-causing genes are believed to have an equivalent in the fly, allowing scientists to explore genetic risk factors for AD.

Dr Gaynor Smith is taking advantage of the fruit fly model to to understand the function of genes that increase the risk of a person developing AD. She is also investigating how processes implicated in ageing may contribute to neurodegeneration – and studying the function of genetic variants that can modify the age-of-onset of another neurodegenerative condition, Huntington’s disease (HD). Her discoveries may lead to effective new treatments that can stop, slow down or reverse the progression of neurodegenerative disorders.

2. Scientific goals

Great insight into the genetic origins of Alzheimer’s disease (AD) have been made possible through recent genome-wide association studies (GWAS), identifying a number of risk variants and avenues for investigation. The goal of Dr Gaynor Smith and her team is to assess if and how these newly-discovered genes contribute to several pathological features in AD including dysregulated neuroimmune interactions, metabolic changes, mitochondrial dysfunction, transcriptional changes and the build-up of amyloid plaques. A specific focus will be to investigate how glia contribute to synaptic loss, the most correlative measure of cognitive decline in patients.

For her investigations, Gaynor is utilising Drosophila (fruit fly) - an excellent model system since many of the genes are conserved and experiments can be conducted at a rapid and relatively inexpensive manner. Once disease-modifying candidate genes are found, the team are using a variety of tools (e.g. GCaMPs, markers for redox and live imaging of organelles) to determine precisely how neuronal physiology has been altered in vivo. Investigating these factors in the adult fly, rather than at larval stages or in vitro, will bypass possible developmental factors that may confound results. They can then further genetically dissect the intracellular pathways linked to AD risk genes - promoting mechanistic insights into AD.

Other research projects include the investigation of ageing and mitochondrial dysfunction in neurodegeneration and functional analysis of genes which modify the age-of-onset in Huntington’s disease.

Main objectives and research goals:

The overarching goal of this Momentum Award is to decipher the contributions of genes associated with dementia, discovered through GWAS and other approaches, to disease progression. The group's aims are:

1. To investigate how new risk genes discovered from GWAS approaches contribute to the pathological mechanisms of Alzheimer’s disease.

2. To determine how changing redox homeostasis affects Alzheimer’s disease progression.

3. To investigate how newly discovered genes which control age-of-onset in Huntington’s disease function at a cell biological level.

4. To discover new genes which contribute to mitochondria ageing in neurons using an unbiased in vivo genetic approach and investigate them in models of Alzheimer’s disease.

3. Team members

Dr Daniel Maddison (Postdoctoral Researcher)
Leonardo Amadio (Research Assistant)
Peta Greer (PhD Student)
Hannah Clarke (PhD Student)
Lucie Tkacova (PhD Student)
Hannah Clarke (PhD Student)
Eve Mogford (PTY Student)

4. Collaborations

Within UK DRI:

Prof Julie Williams, UK DRI at Cardiff
Prof Lesley Jones, UK DRI at Cardiff
Dr Owen Peters, UK DRI at Cardiff
Dr Luke Whiley, UK DRI at Imperial

Beyond UK DRI:

Dr Wynard Van der Goes Van Naters, Cardiff University
Prof Marc Freeman, Oregon Health and Science University
Prof Stephan Zuchner, University of Miami
Prof Hugo Bellen, Baylor Collage of Medicine
Dr James Hodge, Bristol University

5. Topics

Drosophila, Alzheimer’s disease, Huntington’s disease, risk genes, synaptic loss, mitochondria

6. Techniques

Drosophila, GCaMPs, live imaging of organelles, confocal microscopy, immunohistochemistry, genetic crosses, mammalian primary culture, CRISPR, RNAi

7. Key publications

Townsend L.N., Clarke H., Maddison D., Jones K.M., Amadio L. Jefferson A, Chughtai U., Bis D.M., Züchner S., Allen N.D., Van der Goes van Naters W., Peters O.M. & Smith G.A (2023). Cdk12 maintains the integrity of adult axons by suppressing actin remodeling. Cell Death Dis.

Maddison D., Malik B., Amadio L., Bis D.M., Züchner S., Peters O.M. & Smith G.A (2023). COPI-regulated mitochondria-ER contact site formation maintains axonal integrity. Cell Reports. 42 (8).

Rees D., Johnson A.L., Lelos M., Smith G.A., Roberts L.D., Phelps S., Dunnett S.B., Morgan H.A., Brown R.M., Well T. & Davies J (2022). Acyl-ghrelin attenuates neurochemical and motor deficits in the 6-OHDA model of Parkinson’s disease. BioRxiv Preprint.

Lin T-H., Bis-Brewer D.M., Zuchner S. & Smith G.A* & Freeman M* (2021). TSG101 is a negative regulator of mitochondrial biogenesis in axons. PNAS. 118 (20)

Peters O.M., Weiss A., Metterville J., Song L., Logan R., Smith G. A., Schwarzschild M. A., Mueller C., Brown R. H. & Freeman M (2021). Genetic diversity of axon degenerative mechanisms in models of Parkinson's disease. Neurobiology of Disease. 155:105368

Peters O.M & Smith G.A. (2021) A nod and a Wnk to axon branching and destruction. Neuron. 109 (18) 2799-2802

Malik B.R., Maddison D., Smith G.A.* and Peters O.M* (2019). Endolysosomal and autophagy machinery in neurodegenerative disease. Molecular Brain. 12 (100).

Smith, G.A., Lin, T.H., Sheehan, A.E., van Naters, W.V.D.G., Neukomm, L.J., Graves, H.K., Bis-Brewer, D.M., Züchner, S. and Freeman, M.R., 2019. Glutathione S-Transferase Regulates Mitochondrial Populations in Axons through Increased Glutathione Oxidation. Neuron.

Smith, G.A., Jansson, J., Rocha, E.M., Osborn, T., Hallett, P.J. and Isacson, O., 2016. Fibroblast biomarkers of sporadic Parkinson’s disease and LRRK2 kinase inhibition. Molecular neurobiology, 53(8), pp.5161-5177.

Lewis, E.A. and Smith, G.A., 2016. Using Drosophila models of Huntington's disease as a translatable tool. Journal of neuroscience methods, 265, pp.89-98.

Smith, G.A., Rocha, E.M., Rooney, T., Barneoud, P., McLean, J.R., Beagan, J., Osborn, T., Coimbra, M., Luo, Y., Hallett, P.J. and Isacson, O., 2015. A Nurr1 agonist causes neuroprotection in a Parkinson’s disease lesion model primed with the toll-like receptor 3 dsRNA inflammatory stimulant poly (I: C). PLoS One, 10(3), p.e0121072.

Smith, G.A., Rocha, E.M., McLean, J.R., Hayes, M.A., Izen, S.C., Isacson, O. and Hallett, P.J., 2014. Progressive axonal transport and synaptic protein changes correlate with behavioral and neuropathological abnormalities in the heterozygous Q175 KI mouse model of Huntington's disease. Human molecular genetics, 23(17), pp.4510-4527.