Including tau inclusions | Nature Neuroscience


Play all audios:

Access through your institution Buy or subscribe Neurons derived from human induced pluripotent stem cells (hIPSCs) hold great potential for unravelling the pathological mechanisms


underlying neurological diseases. However, when it comes to tauopathies, hIPSC models are limited by their low expression of 4R tau and difficulty in reproducing the characteristic


pathological tau protein inclusions. In a study published in _Cell_, Parra Bravo, Giani et al. used CRISPR–Cas9 gene editing to express 4R tau carrying the highly aggregate-prone MAPT P301S


mutation in hIPSC-derived neurons (4R-P301S). Upon seeding with tau fibrils, these 4R-P301S neurons showed robust tau aggregation and propagation. Neurons harboring tau inclusions displayed


reduced firing activity and evidence of endolysosomal dysfunction, in keeping with tauopathy phenotypes. Applying a CRISPRi screen to their new hIPSC models, the authors identified potential


modifiers of tau propagation, including genes involved in UFMylation. Disrupting the UFMylation cascade reduced the spread of tau inclusions both in the 4R-P301S hIPSC-derived neurons and


in an in vivo mouse model. These newly engineered hIPSC lines could be used to investigate other aspects of tau pathology, such as the mechanisms of tau propagation across cells or how


different tau strains give rise to different tauopathies. ORIGINAL REFERENCE: _Cell_ https://doi.org/10.1016/j.cell.2024.03.015 (2024) This is a preview of subscription content, access via


your institution ACCESS OPTIONS Access through your institution Access Nature and 54 other Nature Portfolio journals Get Nature+, our best-value online-access subscription $29.99 / 30 days


cancel any time Learn more Subscribe to this journal Receive 12 print issues and online access $209.00 per year only $17.42 per issue Learn more Buy this article * Purchase on SpringerLink *


Instant access to full article PDF Buy now Prices may be subject to local taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional


subscriptions * Read our FAQs * Contact customer support AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Nature Neuroscience https://www.nature.com/neuro/ Rebecca Wright Authors * Rebecca


Wright View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Rebecca Wright. RIGHTS AND PERMISSIONS Reprints and


permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Wright, R. Including tau inclusions. _Nat Neurosci_ 27, 811 (2024). https://doi.org/10.1038/s41593-024-01656-w Download citation * Published:


09 May 2024 * Issue Date: May 2024 * DOI: https://doi.org/10.1038/s41593-024-01656-w SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get


shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative