Modeling diseases of noncoding unstable repeat expansions using mutant pluripotent stem cells

Area of Science:

• Genetics
• Molecular Biology
• Neuroscience

Background:

• Pathogenic mutations in DNA repeat expansions lead to over 20 neuronal and neuromuscular diseases.
• These diseases stem from unstable repetitive DNA sequences that expand beyond a critical length.
• Most are autosomal dominant conditions exhibiting anticipation, a phenomenon where disease severity increases with successive generations.

Purpose of the Study:

• To review the contribution of mutant pluripotent stem cells to understanding unstable repeat pathologies.
• Focus on large unstable noncoding expansions and associated diseases.
• Summarize stem cell model applications for investigating disease mechanisms.

Main Methods:

• Review of current literature on stem cell models for unstable repeat expansion disorders.
• Focus on specific diseases including Fragile X syndrome, myotonic dystrophies, Friedreich ataxia, and C9-related ALS/FTD.
• Analysis of common pathogenic mechanisms: RNA toxic gain-of-function, epigenetic loss-of-function, repeat-associated non-ATG translation, and somatic instability.

Main Results:

• Pluripotent stem cells, including human embryonic stem cells and induced pluripotent stem cells, are valuable models for studying these diseases.
• Stem cell models have elucidated mechanisms such as RNA toxicity, epigenetic alterations, and non-canonical translation.
• These models demonstrate significant somatic instability in expanded repeat tracts.

Conclusions:

• Mutant pluripotent stem cells provide critical insights into the pathogenesis of large unstable noncoding repeat expansion diseases.
• Understanding these mechanisms through stem cell research is crucial for developing future therapeutic strategies.
• Further utilization of stem cell models will advance the study of these complex genetic neurological disorders.