Xu, D;
Vincent, A;
González-Gutiérrez, A;
Aleyakpo, B;
Anoar, S;
Giblin, A;
Atilano, ML;
... Niccoli, T; + view all
(2023)
A monocarboxylate transporter rescues frontotemporal dementia and Alzheimer's disease models.
PLoS genetics
, 19
(9)
, Article e1010893. 10.1371/journal.pgen.1010893.
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Abstract
Brains are highly metabolically active organs, consuming 20% of a person's energy at resting state. A decline in glucose metabolism is a common feature across a number of neurodegenerative diseases. Another common feature is the progressive accumulation of insoluble protein deposits, it's unclear if the two are linked. Glucose metabolism in the brain is highly coupled between neurons and glia, with glucose taken up by glia and metabolised to lactate, which is then shuttled via transporters to neurons, where it is converted back to pyruvate and fed into the TCA cycle for ATP production. Monocarboxylates are also involved in signalling, and play broad ranging roles in brain homeostasis and metabolic reprogramming. However, the role of monocarboxylates in dementia has not been tested. Here, we find that increasing pyruvate import in Drosophila neurons by over-expression of the transporter bumpel, leads to a rescue of lifespan and behavioural phenotypes in fly models of both frontotemporal dementia and Alzheimer's disease. The rescue is linked to a clearance of late stage autolysosomes, leading to degradation of toxic peptides associated with disease. We propose upregulation of pyruvate import into neurons as potentially a broad-scope therapeutic approach to increase neuronal autophagy, which could be beneficial for multiple dementias.
| Type: | Article |
|---|---|
| Title: | A monocarboxylate transporter rescues frontotemporal dementia and Alzheimer's disease models |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1371/journal.pgen.1010893 |
| Publisher version: | https://doi.org/10.1371/journal.pgen.1010893 |
| Language: | English |
| Additional information: | © 2023 Xu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/). |
| Keywords: | Humans, Animals, Frontotemporal Dementia, Alzheimer Disease, Neuroglia, Pyruvic Acid, Drosophila, Glucose |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Genetics, Evolution and Environment |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10178001 |
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