Cytoplasmic Accumulation of Histones Induced by BET Inhibition Protects Cells from C9orf72

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The paper we discuss today focuses on the role of dipeptide repeats, particularly poly(proline-arginine), generated from GGGGCC repeat expansions in the C9orf72 gene. These dipeptides are involved in familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in carriers of certain C9orf72 gene variants.

The study indicates that the evolution of cells carrying certain sequence repeats of the C9orf72 gene (called PR20), is influenced by the distribution of these sequences in the nucleus. But the important point from the point of view of patients and caregivers is that these sequences can be hindered by a nuclear import inhibitor called importazole. As importazole can block the nuclear import of PR20, it suggests that the nuclear localization of PR20 is crucial for its cytotoxic effects. Yet importazole is not a clinically approved drug, the use of importazole is mainly confined to laboratory research to understand cellular functions that involve nuclear transport. enter image description here In their search for drugs, the scientists investigated BRD4 inhibitors, such as JQ-1 and I-BET762, which restrict the cytoplasmic localization of the PR20 dipeptide of the C9orf72 gene, and thus diminish its cytotoxic effects. BRD4 is involved in the regulation of transcription and the transmission of epigenetic information during cell division.

In 2016, BRD4 was found to possess histone acetyltransferase activity. Histones are essential components of chromatin and play a crucial role in gene regulation. They act like spools around which DNA winds to create structural units called nucleosomes. The nucleosomes are in turn enveloped in very compact chromatin. Histones also protect DNA against possible damage.

The ability of histone acetyltransferases to manipulate chromatin structure makes them essential for cell maintenance and survival, but they have also been implicated in the progression of neurodegenerative diseases.

Inhibition of BRD4 results in increased expression of histones, causing their accumulation in the cytoplasm. These cytoplasmic histones limit the distribution in the nucleus of the PR20 dipeptide derived from the C9orf72 gene.

I-BET762 is a bromodomain and extraterminal (BET) inhibitor. BET inhibitors specifically target bromodomains, which interact with histone proteins. JQ1 is a thienotriazolodiazepine and another potent inhibitor of the BET family of bromodomain proteins.

Interestingly, the introduction of histones alone is sufficient to protect the cells of the dipeptide derived from repeat sequences from cell death induced by the C9orf72 gene.

Phenylephrine, a drug used to treat nasal congestion, also induces cellular hypertrophy and cytoplasmic distribution of histones, providing additional protection against the PR20 dipeptide of the C9orf72 gene.

The researchers propose that temporary induction of the presence of cytoplasmic histones may attenuate the neurotoxic effects of dipeptide repeat proteins.

A problem is that some BRD4 inhibitors have a short half-life in the body, which would require almost continuous administration. On the other hand, phenylephrine is a medication commonly used as a decongestant, but cannot be used by people with hypertension.

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