# Establishment of a second-generation transgenic marmoset with germline transmission that models polyglutamine disease

## TL;DR

Scientists created a second-generation transgenic marmoset model for a neurodegenerative disease that shows human-like symptoms and pathology, offering a better tool for studying and treating such diseases.

## Contribution

A second-generation transgenic marmoset model with germline transmission for polyglutamine disease was established, showing improved genetic stability and disease phenotypes.

## Key findings

- Five offspring inherited the transgene with fewer integration sites and no genetic instability.
- Three marmosets developed progressive motor impairments with distinct onset patterns and associated physiological changes.
- Pathological features included Purkinje cell loss and intranuclear inclusions, correlating with transgene expression levels.

## Abstract

Neurodegenerative diseases, including polyglutamine diseases, remain a clinical challenge, partly because of limited animal models that recapitulate human disease. Here, we describe a second-generation transgenic marmoset model of spinocerebellar ataxia 3 (SCA3), a polyglutamine disease, which stably expresses expanded CAG repeats in ataxin 3 (ATXN3). All five offspring of the founder marmoset harbored the transgene with reduced transgene integration sites compared with the founder and without repeat instability or genetic mosaicism, offering improved construct validity. Three of the five marmosets developed progressive motor impairments that segregated into two distinct phenotypes – early onset with rapid progression and late onset with mild progression – accompanied by corresponding patterns in body weight gain and grip strength. Pathological analysis revealed cerebellar Purkinje cell loss, spinal cord neurodegeneration and widespread intranuclear inclusions. The severity of motor phenotypes correlated with transgene expression levels in disease-relevant brain regions, including the cerebellum and spinal cord. By overcoming the translational limitations of rodent systems, our second-generation model offers a powerful platform for investigating disease mechanisms and testing potential therapeutics, advancing the utility of transgenic marmosets as clinically relevant models of neurodegenerative diseases.

Summary: Second-generation transgenic marmoset models of spinocerebellar ataxia 3 replicated the progressive motor deficits and neuropathology of the founder marmoset, providing a powerful platform for studying disease mechanisms and developing therapies.