Heterochromatin anomalies and double-stranded RNA accumulation underlie C9orf72 poly(PR) toxicity.

ABSTRACT: How hexanucleotide GGGGCC (G₄C₂) repeat expansions in C9orf72 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 G₄C₂ repeats. The expression of green fluorescent protein-conjugated (PR)₅₀ (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 histon

SUBMITTER: Zhang YJ 

PROVIDER: S-EPMC6524780 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature