Teresa Niccoli (United Kingdom)
University College London
Genetics, Evolution and Environment
I am an ARUK Senior Research Fellow at the Institute of Healthy Ageing (IHA) in the Department of Genetics, Evolution and Environment (GEE). I obtained my PhD in 2002 from the laboratory of Paul Nurse at Cancer Research UK, investigating cell polarity in S. pombe. I then joined the laboratory of Daniel St Johnson at the Gurdon Institute in Cambridge as a Beit Memorial Fellow, looking at polarity during Drosophila oogenesis. I then took a career break to look after my two sons and completed a Master’s in Medical Ethics and Law at King’s College, London in 2009. In 2010 I joined the laboratory of Prof Linda Partridge at the Institute of Healthy Ageing (IHA) at UCL to work on Drosophila models of neurodegenerative diseases and then moved to Adrian Isaacs laboratory at the Dementia Research Centre at UCL. In 2019 I started my own group using Drosophila models to study dementia, in particular looking at the link between metabolism and neuronal cell death. In January 2019 I came back to the IHA to start my own group working on Drosophila models of dementia.

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 Conference Calendar

A MONOCARBOXYLATE TRANSPORTER AS A MODIFIER OF C9ORF72 REPEAT EXPANSION TOXICITY

Session Name
0410 - TDP43- AND C9ORF72-RELATED DISEASES 1 (ID 60)
Session Type
SYMPOSIUM
Date
Wed, 16.03.2022
Session Time
04:15 PM - 06:15 PM
Room
ONSITE: 133-134
Lecture Time
05:15 PM - 05:30 PM
Presenter

Abstract

Aims

A hexanucleotide repeat expansion within the C9orf72 gene (C9) is the primary genetic cause of Amyotrophic lateral sclerosis (ALS) and Frontotemporal dementia (FTD). Toxicity in neurons at least partly results from the production of dipeptide repeat proteins (DPR) which are translated via non canonical non- ATG initiated translation. To try to understand the mechanisms leading to neuronal death we have developed a Drosophila melanogaster model expressing 36 hexanucleotide repeats (36R). This model displays neuronal toxicity and a shortened lifespan. We have carried out a large scale genetic screen and identified a number of suppressors of toxicity. We are now characterising one of these, a monocarboxylate transporter.

Methods

We have carried out lifespans and behavioural assays in Drosophila, together with ELISAs for the different DPRs produced by the expansion to evaluate the effect of the transporter on the health of the C9 model and on the toxic DPRs.

Results

The monocarboxylate transporter we have identified, when over-expressed, leads to a substantial rescue of toxicity and to a reduction in the levels of the toxic peptides associated with the repeats. This transporter can import lactate and pyruvate, two known suppressors of histone deacetylases (HDACs). We have identified significant changes in acetylation patterns following the expression of the transporter.

We are in the process of understanding how this rescue is mediated and whether modulation of HDACs is a mediator of this rescue.

Conclusions

Over-expression of a monocarboxylate transporter can rescue C9 repeat expansion toxicity, possibly by modulating HDAC activation.

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