Projects
Mitochondrial Neurobiology
To discover new genes which control mitochondria maintenance in the axons of neurons using an unbiased in vivo genetic approach.
We know relatively little about the basic biology of mitochondrial biogenesis, morphological changes, transport, or function in axons in vivo, yet mitochondrial abnormalities in the terminals have been strongly linked to the etiology of several neurodegenerative disorders. We perform unbiased genetic screening in fruit flies to discover new mitochondrial regulators in axons and characterize their function. Mitochondrial mechanisms and dynamics are applicable to neurodegenerative disease and axonopathies, where mitochondrial dysfunction is typically an early feature. Other interests include understanding how mitochondria “communicate” with other organelles such as peroxisomes and endoplasmic reticulum to drive metabolic processes.
Neurodegenerative disease research
To investigate how new genes discovered from GWAS approaches contribute to the pathological mechanisms of Alzheimer’s disease.
The number of people living with dementia in the UK is forecast to increase to approximately 1 million by 2025 and over 2 million by 2051 (https://www.alzheimers.org.uk/) and there is currently no treatment that can help slow down disease progression. Key pathological features of the disease are dysregulated neuroimmune interactions, metabolic changes, transcriptional changes and the build up of amyloid plaques. Insights into the genetic origins of Alzheimer’s disease have been made through Genome Wide Association Studies (GWAS). Our lab is interested in understanding how the key genes contribute to Alzheimer’s disease using Drosophila. Approximately 70% of disease associated genes are conserved beween humans and the fly. This gives us an opppotunity to discover how risk genes may alter neurobiology, pathology, behaviour and longevity.
Group Members
Dr Daniel Maddison (Post Doctoral Research Associate)
Leonardo Amadio (Research Assistant)
Peta Greer (PhD Student)
Hannah Clarke (PhD Student)
Lucie Tkacova (PhD Student)
Alumni
Dr Freya Storer (Former PhD Student)
Dr Freja Saddler (Former PhD Student)
Dr Louise Townsend (Former PhD Student)
Key publications
Maddison D., Malik B., Amadio L., Bis D.M., Züchner S., Peters O.M. & Smith G.A (2023). COPI-regulated Mitochondria-ER contact formation maintains Axon Integrity. Cell Reports. 42 (8)
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)
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. 103 (1)
