Microsatellite Expansion Diseases: Repeat Toxicity Found in Translation

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder.
• The disease is associated with expanded CGG repeats in the FMR1 gene.
• The precise pathogenic mechanism of expanded CGG repeats in FXTAS remains incompletely understood.

Purpose of the Study:

• To investigate the translation of expanded CGG repeats in FXTAS.
• To determine the role of the translated protein versus repeat RNA in FXTAS pathogenesis.
• To identify the initiation site of translation for expanded CGG repeats.

Main Methods:

• Analysis of patient-derived cells and animal models.
• RNA sequencing and protein analysis.
• Investigation of translation initiation using reporter assays.

Main Results:

• Translation of expanded CGG repeats is initiated at an upstream ACG near-cognate start codon.
• The resulting protein contains a polyglycine tract.
• This polyglycine-containing protein, not the repeat RNA, is pathogenic and disrupts the nuclear lamina.

Conclusions:

• Translation of expanded CGG repeats contributes to FXTAS pathogenesis.
• The pathogenic mechanism involves a polyglycine-containing protein that disrupts nuclear lamina structure.
• Targeting this translation product may offer therapeutic strategies for FXTAS.