ArticleGenomic psychiatry : advancing science from genes to society2025
The deubiquitinase OTULIN regulates tau expression and RNA metabolism in neurons.
Article in Genomic psychiatry : advancing science from genes to society, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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2 citing papers in PubMed.
- Atypical involvement of Alzheimer's tau proteins in diseases beyond tauopathies.Life medicine · 2026Review
- Tau protein: Physiological functions and multifaceted roles in neurodegenerative and psychiatric disorders.Genomic psychiatry : advancing science from genes to society · 2025Article
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6 authors.
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Abstract
The degradation of aggregation-prone tau is regulated by the ubiquitin-proteasome system (UPS) and autophagy, which are impaired in Alzheimer's disease (AD) and related dementias (ADRD), causing tau aggregation. Protein ubiquitination, with its linkage specificity determines the fate of proteins, which can be either protein degradative or stabilizing signals. While the linear M1-linked ubiquitination on protein aggregates serves as a signaling hub that recruits various ubiquitin-binding proteins for the coordinated actions of protein aggregate turnover and inflammatory NF-κB activation, the deubiquitinase OTULIN counteracts the M1-linked ubiquitin signaling. However, the exact role of OTULIN in neurons and tau aggregates clearance in AD are unknown. Based on our quantitative bulk RNA sequence analysis of human inducible pluripotent stem cell (iPSC)-derived neurons (iPSNs) from an individual with late-onset sporadic AD (sAD2.1), a downregulation of the ubiquitin ligase activating factors (MAGE-A2/A2B/H1) and OTULIN long non-coding RNA (OTULIN lncRNA) was observed compared to healthy control WTC11 iPSNs. The down-regulated OTULIN lncRNA is concurrently associated with increased levels of OTULIN protein and phosphorylated tau at p-S202/p-T205 (AT8), p-T231 (AT180), and p-S396/p-S404 (PHF-1) in sAD2.1 iPSNs. Inhibiting the deubiquitinase activity of OTULIN with a small molecule, UC495 reduced the phosphorylated tau in iPSNs and SH-SY5Y cells, whereas the CRISPR-Cas9-mediated
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