Maffei, Benito;
Lignani, Gabriele;
(2022)
One to Rule Them All: A Unique TAU Therapy for Neurodevelopmental Encephalopathies.
Epilepsy Currents
, 22
(6)
10.1177/15357597221126332.
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Abstract
TAU Ablation in Excitatory Neurons and Postnatal TAU Knockdown Reduce Epilepsy, SUDEP, and Autism Behaviors in a Dravet Syndrome Model Shao E, Chang C-W, Li Z, Yu X, Ho K, Zhang M, Wang X, Simms J, Lo I, Speckart J, Holtzman J, Yu G-Q, Roberson ED, Mucke L. Sci Transl Med. 2022;14(642):eabm5527. doi:10.1126/scitranslmed.abm5527 Intracellular accumulation of TAU aggregates is a hallmark of several neurodegenerative diseases. However, global genetic reduction of TAU is beneficial also in models of other brain disorders that lack such TAU pathology, suggesting a pathogenic role of nonaggregated TAU. Here, conditional ablation of TAU in excitatory, but not inhibitory, neurons reduced epilepsy, sudden unexpected death in epilepsy, overactivation of the phosphoinositide 3-kinase-AKT-mammalian target of rapamycin pathway, brain overgrowth (megalencephaly), and autism-like behaviors in a mouse model of Dravet syndrome, a severe epileptic encephalopathy of early childhood. Furthermore, treatment with a TAU-lowering antisense oligonucleotide, initiated on postnatal day 10, had similar therapeutic effects in this mouse model. Our findings suggest that excitatory neurons are the critical cell type in which TAU has to be reduced to counteract brain dysfunctions associated with Dravet syndrome and that overall cerebral TAU reduction could have similar benefits, even when initiated postnatally.
| Type: | Article |
|---|---|
| Title: | One to Rule Them All: A Unique TAU Therapy for Neurodevelopmental Encephalopathies |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1177/15357597221126332 |
| Publisher version: | https://doi.org/10.1177/15357597221126332 |
| Language: | English |
| Additional information: | This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third-party material in this article are included in the Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Experimental Epilepsy UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10156532 |
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