Transgenic Monkey Model of the Polyglutamine Diseases Recapitulating Progressive Neurological Symptoms

Area of Science:

• Neuroscience
• Genetics
• Primatology

Background:

• Age-associated neurodegenerative diseases like Alzheimer's, Parkinson's, and polyglutamine (polyQ) diseases are increasing due to longer lifespans.
• Existing rodent models have limitations in translational utility for human neurodegenerative diseases due to species-specific differences.

Purpose of the Study:

• To develop a novel transgenic marmoset model for polyglutamine (polyQ) diseases.
• To assess the translational potential of this marmoset model for studying neurodegenerative disease mechanisms and therapies.

Main Methods:

• Generated transgenic marmosets via lentiviral introduction of the human ataxin 3 gene with an expanded 120 CAG repeat polyQ stretch.
• Monitored offspring for neurological symptoms, physical changes, and disease progression from birth.
• Conducted pathological examinations, including brain MRI, and assessed germline transgene transmission.

Main Results:

• Transgenic marmosets with higher transgene expression developed progressive neurological symptoms, including motor impairment, decreased activity, and weight loss, starting at 3-4 months.
• Pathological findings revealed neurodegeneration, intranuclear polyQ inclusions, and gliosis, mirroring human polyQ disease neuropathology.
• Brain MRI indicated cerebellar atrophy, and germline transmission was confirmed in the second generation.

Conclusions:

• The transgenic marmoset model accurately recapitulates key features of human polyQ diseases.
• This model provides a valuable platform for investigating the pathomechanisms of neurodegenerative diseases.
• The marmoset model holds promise for developing effective, clinically applicable therapies for polyglutamine and related neurodegenerative disorders.