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...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2023-09-01
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| Series: | PLoS Genetics |
| Online Access: | https://doi.org/10.1371/journal.pgen.1010893 |
| _version_ | 1797672681285353472 |
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| author | Dongwei Xu Alec Vincent Andrés González-Gutiérrez Benjamin Aleyakpo Sharifah Anoar Ashling Giblin Magda L Atilano Mirjam Adams Dunxin Shen Annora Thoeng Elli Tsintzas Marie Maeland Adrian M Isaacs Jimena Sierralta Teresa Niccoli |
| author_facet | Dongwei Xu Alec Vincent Andrés González-Gutiérrez Benjamin Aleyakpo Sharifah Anoar Ashling Giblin Magda L Atilano Mirjam Adams Dunxin Shen Annora Thoeng Elli Tsintzas Marie Maeland Adrian M Isaacs Jimena Sierralta Teresa Niccoli |
| author_sort | Dongwei Xu |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-11T21:33:42Z |
| format | Article |
| id | doaj.art-44d952c3a1cc4820a8897d05251cf851 |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-03-11T21:33:42Z |
| publishDate | 2023-09-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-44d952c3a1cc4820a8897d05251cf8512023-09-27T05:31:18ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042023-09-01199e101089310.1371/journal.pgen.1010893A monocarboxylate transporter rescues frontotemporal dementia and Alzheimer's disease models.Dongwei XuAlec VincentAndrés González-GutiérrezBenjamin AleyakpoSharifah AnoarAshling GiblinMagda L AtilanoMirjam AdamsDunxin ShenAnnora ThoengElli TsintzasMarie MaelandAdrian M IsaacsJimena SierraltaTeresa NiccoliBrains 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.https://doi.org/10.1371/journal.pgen.1010893 |
| spellingShingle | Dongwei Xu Alec Vincent Andrés González-Gutiérrez Benjamin Aleyakpo Sharifah Anoar Ashling Giblin Magda L Atilano Mirjam Adams Dunxin Shen Annora Thoeng Elli Tsintzas Marie Maeland Adrian M Isaacs Jimena Sierralta Teresa Niccoli A monocarboxylate transporter rescues frontotemporal dementia and Alzheimer's disease models. PLoS Genetics |
| 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 |
| url | https://doi.org/10.1371/journal.pgen.1010893 |
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