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An AMPK-dependent regulatory pathway in tau-mediated toxicity
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Galasso, Alessia, Cameron, Charles S., Frenguelli, Bruno G. and Moffat, Kevin G. (2017) An AMPK-dependent regulatory pathway in tau-mediated toxicity. Biology Open, 6 (10). pp. 1434-1444. doi:10.1242/bio.022863
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Official URL: http://dx.doi.org/10.1242/bio.022863
Abstract
Neurodegenerative tauopathies are characterized by accumulation of hyperphosphorylated tau aggregates primarily degraded by autophagy.
The 5'AMP-activated protein kinase (AMPK) is expressed in most cells, including neurons. Alongside its metabolic functions, it is also known to be activated in Alzheimer's brains, phosphorylate tau and be a critical autophagy activator. Whether it plays a neurotoxic or neuroprotective role remains unclear. Complexly in tauopathies, while stress conditions can result in AMPK activation enhancing tau-mediated toxicity, AMPK activation is not always concomitant with autophagic induction.
Using a Drosophila in vivo quantitative approach, we have analysed the impact of AMPK and autophagy on tau-mediated toxicity, recapitulating the AMPK-mediated tauopathy condition: increased tau phosphorylation, without corresponding autophagy activation.
We have demonstrated that AMPK, binding to and phosphorylating tau at Ser-262, a site reported to facilitate soluble tau accumulation, affects its degradation. This phosphorylation results in exacerbation of tau toxicity and is ameliorated via rapamycin-induced autophagy stimulation.
Our findings support the development of combinatorial therapies effective at reducing tau toxicity targeting tau phosphorylation and AMPK-independent autophagic induction. The proposed in vivo tool represents an ideal readout to perform preliminary screening for drugs promoting this process.
| Item Type: | Journal Article | ||||||||
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| Subjects: | Q Science > QP Physiology | ||||||||
| Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | ||||||||
| Library of Congress Subject Headings (LCSH): | Protein kinases, Microtubules, Drosophila, Cell death, Phosphorylation | ||||||||
| Journal or Publication Title: | Biology Open | ||||||||
| Publisher: | The Company of Biologists Ltd. | ||||||||
| ISSN: | 2046-6390 | ||||||||
| Official Date: | 15 October 2017 | ||||||||
| Dates: |
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| Volume: | 6 | ||||||||
| Number: | 10 | ||||||||
| Page Range: | pp. 1434-1444 | ||||||||
| DOI: | 10.1242/bio.022863 | ||||||||
| Status: | Peer Reviewed | ||||||||
| Publication Status: | Published | ||||||||
| Access rights to Published version: | Open Access | ||||||||
| Funder: | National Centre for the Replacement, Refinement, and Reduction of Animals in Research (Great Britain) (NC3R) | ||||||||
| Grant number: | G0900801/91180 (NC3R) |
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