Histone deacetylase inhibitors reduce polyglutamine toxicity

Area of Science:

• Neurodegenerative diseases
• Molecular biology
• Genetics

Background:

• Polyglutamine diseases are a group of nine neurodegenerative disorders caused by CAG repeat expansions in various genes.
• Mutant polyglutamine protein accumulation is observed in patients, with the nucleus implicated as a key site of pathogenesis.
• Understanding the nuclear consequences of polyglutamine accumulation is crucial for developing therapeutic strategies.

Purpose of the Study:

• To investigate the effects of nuclear polyglutamine accumulation on neuronal cells.
• To identify mechanisms underlying cell death in polyglutamine diseases.
• To explore potential therapeutic interventions targeting protein acetylation.

Main Methods:

• Development of a cell culture system with nuclear-targeted polyglutamine.
• Assessment of cell death mitigation through overexpression of cAMP response element binding protein (CREB)-binding protein (CBP) or its amino-terminal portion.
• Analysis of histone acetylation levels in cells expressing mutant polyglutamine.
• Evaluation of the impact of deacetylase inhibitors on cell loss.

Main Results:

• Overexpression of CBP or its amino terminus significantly mitigated cell death in the cell culture system.
• Histone acetylation was found to be reduced in cells with mutant polyglutamine expression.
• Reversing hypoacetylation through CBP overexpression or deacetylase inhibitor treatment reduced neuronal cell loss.
• CBP, a histone acetyltransferase, is sequestered by polyglutamine inclusions.

Conclusions:

• Nuclear accumulation of polyglutamine proteins disrupts normal protein acetylation in neurons.
• Altered histone acetylation is a key factor in the pathogenesis of polyglutamine diseases.
• Targeting protein acetylation represents a promising therapeutic strategy for polyglutamine diseases.