Dr Gaynor Ann Smith

Dr Gaynor Ann Smith

Lecturer, Dementia Research Institute

School of Medicine

Email:
smithga@cardiff.ac.uk
Location:
1.03, Office F, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ

Molecular mechanisms of neurodegenerative disease

Neurodegenerative disorders such as Alzheimer’s, Parkinson’s and Huntington’s diseases are incurable and debilitating conditions that result in the progressive degeneration of different neuronal populations. Mitochondrial dysfunction, protein aggregation and altered glial responses are unifying features across these diseases and even manifest in prodromal stages.  My laboratory is interested in understating the conserved molecular and cellular mechanisms underpinning these basic neurobiological processes, from Drosophila to humans.

Research Goals

  1. To discover new genes which control mitochondria maintenance in neurons using an unbiased in vivo genetic approach.
  2. To investigate how new genes discovered from GWAS approaches contribute to the pathological mechanisms of Alzheimer’s disease.
  3. To determine how changing redox homeostasis affects Alzheimer’s and Huntington’s disease progression.

I obtained my BSc in Physiology from Cardiff University and remained there to completed my PhD in the laboratory of Prof. Stephan Dunnett where I focused on understanding how treatment strategies such as cell transplantation and L-DOPA therapy effected the phenotypic outcome of Parkinson’s models.

I began my post-doctoral training at Harvard Medical School in the laboratory of Prof. Ole Isacson where I characterized the histopathological and behavioural deficits in the Q175 mouse model of Huntington’s disease, and used gene therapy stratagies and small molecule administration to mitigate phenotypes in rodent models of Parkinson’s disease. I further studied several mitochondrial phenotypes in Parkinson’s patient and control tissue samples that were exposed to mitochondrial specific toxins. This drove differential changes in mitochondrial morphology, LRRK2 phosphorylation, reactive oxygen species generation, mitochondrial membrane potential and mitophagy levels.

During my second post-doctoral position in the laboratory of Prof. Marc Freeman, first based at the University of Massachusetts then moving to Oregon Health and Science University I continued to study mitochondria in Drosophila and screened for new modifiers of mitochondrial dynamics in neurons.

My own research group at Cardiff University will continue to study mitochondrial dynamics in neurons and investigate genetic modifiers of Alzheimer’s disease and Huntington’s disease.

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Research Goals

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.

Neuronal health is maintained by the balance between constant degradation of damaged mitochondria through mitophagy and biogenesis. These pathways are highly conserved from humans to invertebrates. Mitophagy requires the coordinated action of PINK1 and Parkin and the genetic interaction of these two molecules was discovered using Drosophila (Park et al., 2006).

Work from Drosophila also revealed that two key proteins, Miro and Milton, are needed to transport mitochondria and orchestrate their disengagement from the cytoskeleton in areas of high Ca2+ to enhance buffering (reviewed by Tang, 2016).

Mitochondria are also highly dynamic in the axon and undergo constant fusion and fission to share or avoid mixing mtDNA and proteins depending on the status of the neuron. OPA-1, Marf, Drp1 and Fis1 have so far been discovered as the main regulators of fission/ fusion balance.

My lab performs unbiased genetic screening in fruit flies to discover new mitochondrial regulators in axons, which may be applicable to neurodegenerative disease and characterize their function. Other interests include understanding how mitochondria “communicate” with other organelles such as peroxisomes and endoplasmic reticulum to drive metabolic processes.

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), in which Cardiff University has played a major role, spearheaded by Prof. Julie Williams.

My lab, in collaboration with Dr Owen Peters and members of the Dementia Research Institute (DRI) will focus on understanding the genetics of these key pathological processes that contribute to Alzheimer’s disease using Drosophila and information gathered through GWAS.

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

Free radicals generated by mitochondria can become harmful to neurons unless they are quenched by antioxidants.

My lab is interested in understating how molecules involved in redox status contribute to neurodegeneration, with specific focus on peroxidases, transferases and reductases that reside either within the mitochondria or axoplasm.

External profiles