Heterochromatin anomalies and double-stranded RNA accumulation underlie <i>C9orf72</i> poly(PR) toxicity.
basic_science · Level V
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- Record sourced from PubMed, PMID 30765536.
- Also identified by DOI 10.1126/science.aav2606 and PMC identifier 6524780.
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Abstract
How hexanucleotide GGGGCC (G<sub>4</sub>C<sub>2</sub>) repeat expansions in <i>C9orf72</i> cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is not understood. We developed a mouse model engineered to express poly(PR), a proline-arginine (PR) dipeptide repeat protein synthesized from expanded G<sub>4</sub>C<sub>2</sub> repeats. The expression of green fluorescent protein-conjugated (PR)<sub>50</sub> (a 50-repeat PR protein) throughout the mouse brain yielded progressive brain atrophy, neuron loss, loss of poly(PR)-positive cells, and gliosis, culminating in motor and memory impairments. We found that poly(PR) bound DNA, localized to heterochromatin, and caused heterochromatin protein 1α (HP1α) liquid-phase disruptions, decreases in HP1α expression, abnormal histone methylation, and nuclear lamina invaginations. These aberrations of histone methylation, lamins, and HP1α, which regulate heterochromatin structure and gene expression, were accompanied by repetitive element expression and double-stranded RNA accumulation. Thus, we uncovered mechanisms by which poly(PR) may contribute to the pathogenesis of <i>C9orf72</i>-associated FTD and ALS.
Medical subject headings
- Amyotrophic Lateral Sclerosis
- C9orf72 Protein
- Dipeptides
- Heterochromatin
- RNA, Double-Stranded