Research squareOct 3, 2025

A mouse with extra human Staufen1 protein shows abnormal cell recycling and nerve cell loss throughout the brain and spinal cord

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jan 7, 2026

Abstract

STAU1 overabundance is associated with impaired autophagic flux and abnormal protein responses in various neurodegenerative disease models.

STAU1 regulates mRNA degradation and subcellular localization as part of the ATXN2 protein complex.
Increased levels of STAU1 were found in patient fibroblasts and mouse models of Alzheimer's disease, ALS, and spinocerebellar ataxia type 2.
STAU1 overabundance leads to the accumulation of biomolecular condensates and disrupts the unfolded protein response.
Expression of the human STAU1 gene in a mouse model resulted in dysregulated gene expression and glial activation.
Reducing STAU1 levels through RNA interference improved the observed molecular abnormalities.
No significant behavioral changes were noted in mice up to 55 weeks of age, indicating STAU1's potential role as a modifier in neuronal degeneration.

Simplified

RNA-binding proteins (RBPs) play an essential role in development, normal functioning and human disease. Staufen1 (STAU1) is an RBP that regulates mRNA degradation and subcellular localization, and is part of the ATXN2 protein complex. Previously, we showed that STAU1 is overabundant in patient fibroblasts and in mouse models of Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and spinocerebellar ataxia type 2 (SCA2), where it is associated with impaired autophagic flux due to STAU1-mediated upregulation of mTOR translation. STAU1 overabundance and impaired autophagy cause accumulation of biomolecular condensates and abnormal unfolded protein response (UPR). We generated a mouse model expressing the entire humangene (h) in a bacterial artificial chromosome (BAC) construct. hSTAU1 in these mice was expressed in cerebral hemispheres, cerebellum and spinal cord, as well as cultured cortical neurons and cortical and spinal cord astrocytes and microglia. Expression of hSTAU1 caused dysregulated gene expression, abnormal autophagy, glial activation, and changes in neuronal marker proteins. All of these were significantly improved by reducing STAU1 abundance by RNAi, but exacerbated in BAC-STAU1 mice crossed with Prp-TDP-43(Q331K) transgenic mice. Similar results were also obtained in eye phenotypes in ALS- and SCA2-relevant fly models upon changing staufen-1 dosage. Despite the molecular changes, we observed no overt behavioral changes in mice up to 55 weeks of age, suggesting that STAU1 may function as an epistatic modifier of neuronal degeneration. The BAC-hSTAU1 mouse will be useful for developing therapies targeting the human STAU1 gene. STAU1STAU1

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A mouse with extra human Staufen1 protein shows abnormal cell recycling and nerve cell loss throughout the brain and spinal cord

Abstract

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