# Polyserine domains are toxic and exacerbate tau pathology in mice

## TL;DR

This study shows that polyserine domains are toxic in mice and worsen tau-related brain diseases.

## Contribution

The study demonstrates for the first time that polyserine expression in the mammalian brain is toxic and exacerbates tau pathology.

## Key findings

- Polyserine expression causes motor impairment and Purkinje cell loss in wild-type mice.
- In tau transgenic mice, polyserine increases phosphorylated and insoluble tau levels.
- Polyserine enhances the seeding capacity of brain extracts in tauopathy models.

## Abstract

This study evaluates the toxic effects of polyserine domains in vivo. Polyserine and endogenous polyserine-containing proteins have been shown to enrich in tau aggregates across models and in human postmortem tissues. Further, polyserine proteins are expressed in the context of CAG repeat expansion diseases such as spinocerebellar ataxia. Through viral-mediated delivery, this study demonstrates that expression of polyserine-containing proteins leads to toxicities in both wild-type and tau transgenic mouse models. Toxic effects independent of genotype include motor impairment and the loss of Purkinje cells in the cerebellum. Further, in mice expressing human mutant tau, polyserine expression exacerbates markers of tau pathology. These results support further investigation of polyserine in the pathogenesis of tauopathies and CAG repeat expansion disorders.

Polyserine domains mediate the association of some nuclear RNA-binding proteins with cytoplasmic tau aggregates occurring in tauopathy models and patient samples. In cell lines, polyserine domains mediate colocalization with tau aggregates and promote formation, suggesting that the cytoplasmic mislocalization of polyserine-containing proteins could contribute to human disease. Moreover, polyserine can be produced by repeat-associated non-AUG translation in CAG repeat expansion diseases. However, whether polyserine expressed in a mammalian brain is toxic and/or can exacerbate tau pathology is unknown. We used AAV9-mediated delivery to express a 42-repeat polyserine protein in wild-type and tau transgenic mouse models. We observe that polyserine expression has toxic effects in wild-type animals indicated by reduced weight, behavioral abnormalities, and a striking loss of Purkinje cells. Moreover, in the presence of a pathogenic variant of human tau, polyserine exacerbates disease markers such as phosphorylated and insoluble tau levels and the seeding capacity of brain extracts. These findings demonstrate that polyserine domains can promote tau-mediated pathology in a mouse model and support the hypothesis that polyserine-containing proteins could contribute to the progression of human tauopathies.