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A monocarboxylate transporter rescues frontotemporal dementia and Alzheimer’s disease models

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...

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Autores principales: Xu, Dongwei, Vincent, Alec, González-Gutiérrez, Andrés, Aleyakpo, Benjamin, Anoar, Sharifah, Giblin, Ashling, Atilano, Magda L., Adams, Mirjam, Shen, Dunxin, Thoeng, Annora, Tsintzas, Elli, Maeland, Marie, Isaacs, Adrian M., Sierralta, Jimena, Niccoli, Teresa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10513295/
https://www.ncbi.nlm.nih.gov/pubmed/37733679
http://dx.doi.org/10.1371/journal.pgen.1010893
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author Xu, Dongwei
Vincent, Alec
González-Gutiérrez, Andrés
Aleyakpo, Benjamin
Anoar, Sharifah
Giblin, Ashling
Atilano, Magda L.
Adams, Mirjam
Shen, Dunxin
Thoeng, Annora
Tsintzas, Elli
Maeland, Marie
Isaacs, Adrian M.
Sierralta, Jimena
Niccoli, Teresa
author_facet Xu, Dongwei
Vincent, Alec
González-Gutiérrez, Andrés
Aleyakpo, Benjamin
Anoar, Sharifah
Giblin, Ashling
Atilano, Magda L.
Adams, Mirjam
Shen, Dunxin
Thoeng, Annora
Tsintzas, Elli
Maeland, Marie
Isaacs, Adrian M.
Sierralta, Jimena
Niccoli, Teresa
author_sort Xu, Dongwei
collection PubMed
description 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.
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spelling pubmed-105132952023-09-22 A monocarboxylate transporter rescues frontotemporal dementia and Alzheimer’s disease models Xu, Dongwei Vincent, Alec González-Gutiérrez, Andrés Aleyakpo, Benjamin Anoar, Sharifah Giblin, Ashling Atilano, Magda L. Adams, Mirjam Shen, Dunxin Thoeng, Annora Tsintzas, Elli Maeland, Marie Isaacs, Adrian M. Sierralta, Jimena Niccoli, Teresa PLoS Genet Research Article 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. Public Library of Science 2023-09-21 /pmc/articles/PMC10513295/ /pubmed/37733679 http://dx.doi.org/10.1371/journal.pgen.1010893 Text en © 2023 Xu et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Xu, Dongwei
Vincent, Alec
González-Gutiérrez, Andrés
Aleyakpo, Benjamin
Anoar, Sharifah
Giblin, Ashling
Atilano, Magda L.
Adams, Mirjam
Shen, Dunxin
Thoeng, Annora
Tsintzas, Elli
Maeland, Marie
Isaacs, Adrian M.
Sierralta, Jimena
Niccoli, Teresa
A monocarboxylate transporter rescues frontotemporal dementia and Alzheimer’s disease models
title A monocarboxylate transporter rescues frontotemporal dementia and Alzheimer’s disease models
title_full A monocarboxylate transporter rescues frontotemporal dementia and Alzheimer’s disease models
title_fullStr A monocarboxylate transporter rescues frontotemporal dementia and Alzheimer’s disease models
title_full_unstemmed A monocarboxylate transporter rescues frontotemporal dementia and Alzheimer’s disease models
title_short A monocarboxylate transporter rescues frontotemporal dementia and Alzheimer’s disease models
title_sort monocarboxylate transporter rescues frontotemporal dementia and alzheimer’s disease models
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10513295/
https://www.ncbi.nlm.nih.gov/pubmed/37733679
http://dx.doi.org/10.1371/journal.pgen.1010893
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