| Title: |
Selective disruption of tau–SH3 interactions rescues seizure and sleep phenotypes |
| Authors: |
Shandilya, M C Vishnu; Koutures, Anne; Addo-Osafo, Kwaku; Hwang, Kaylin; Vicente, Mariane; Ewens, Ashley N; Katz, Brittany M; Peters, Samuel T; Choquette, Jessica M; Vaknalli, Rahil N; Venkateswaran, Nisha; Onanyan, Nane; Narasani, Anushka; Ravishankar, Sahana; Stepter, Joshua; Western, Ava; Benneyworth, Michael A; Cohn, Whitaker; John, Varghese; Whitelegge, Julian P; Vossel, Keith |
| Source: |
Brain ; ISSN 0006-8950 1460-2156 |
| Publisher Information: |
Oxford University Press (OUP) |
| Publication Year: |
2026 |
| Description: |
Alzheimer's disease (AD) patients frequently experience seizures, sleep disturbances, and other forms of neural network dysfunction that accelerate cognitive decline. Although tau-lowering therapies may alleviate these features, they also risk disrupting essential physiological functions of tau, leading to motor impairments. We hypothesized that targeted mutations within tau’s proline-rich domain—regions critical for binding SH3-containing proteins implicated in seizures and excitotoxicity—could selectively disrupt pathological interactions while preserving normal cognition and behaviour. To test this, we generated two tau knockin mouse lines: AxxA6, carrying proline-to-alanine mutations in the sixth PxxP motif, and R221A, containing an arginine-to-alanine substitution at residue 221. Tau-protein interactions were evaluated using proximity ligation assays in cultured hippocampal neurons and co-immunoprecipitation-mass spectrometry of cortical lysates. To model epilepsy, Kv1.1 heterozygous knockout mice were crossed with tau knockin mice. Mice underwent 24-hour cortical EEG recordings. Seizure susceptibility was assessed following intraperitoneal kainic acid (25 mg/kg). Hippocampal slice electrophysiology was used to measure epileptic bursting after picrotoxin/4-AP application. Comprehensive motor and cognitive testing were performed in AxxA6 and R221A lines at young and older ages. Both variants reduced tau’s binding to the SH3-containing proteins BIN1, PLCγ1, and p85⍺/PI3K, with AxxA6 specifically decreasing Fyn interaction (P < 0.0001). Coimmunoprecipitation-mass spectrometry revealed variant-specific alterations in tau interactomes, including increased synaptotagmin-5 binding in both lines (P < 0.05). AxxA6 knockin mice displayed unique resistance to kainic-acid-induced seizures. AxxA6 knockin also reduced epileptic spike rates in Kv1.1-/- mice (P = 0.02), along with improved beta power during REM (P < 0.05), and rescued sleep disruptions (P < 0.002). Both AxxA6 and R221A ... |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1093/brain/awag090 |
| DOI: |
10.1093/brain/awag090/67279683/awag090.pdf |
| Availability: |
https://doi.org/10.1093/brain/awag090; https://academic.oup.com/brain/advance-article-pdf/doi/10.1093/brain/awag090/67279683/awag090.pdf |
| Rights: |
https://creativecommons.org/licenses/by-nc/4.0/ |
| Accession Number: |
edsbas.91CBBC53 |
| Database: |
BASE |