The 26S proteasome drives trinucleotide repeat expansions.

Area of Science:

• Molecular Biology
• Genetics
• Neuroscience

Background:

• Trinucleotide repeat (TNR) expansions cause over 17 inherited neurological disorders.
• Identifying proteins that promote TNR expansion is crucial for understanding disease mechanisms.

Purpose of the Study:

• To identify novel protein factors driving TNR expansions.
• To investigate the role of the 26S proteasome in TNR expansion.

Main Methods:

• Genetic screening in budding yeast to identify suppressors of TNR expansions.
• Analysis of Sem1 protein function and its role in the 26S proteasome.
• Experimental manipulation of proteasome components and activity in yeast and human cell lines.
• siRNA-mediated knockdown of proteasome subunits in human cells.

Main Results:

• The multi-functional protein Sem1 was identified as a novel driver of TNR expansions in yeast, with SEM1 mutants suppressing up to 90% of expansions.
• Sem1 facilitates TNR expansions through its function in the 26S proteasome.
• Inhibition or mutation of 26S proteasome components suppressed CTG•CAG expansions in yeast.
• Knockdown of 26S proteasome subunits (PSMC5, PSMB3) reduced TNR expansions in a human astrocytic cell line.
• The observed expansion phenotype is dependent on the proteolytic activity of the 26S proteasome.

Conclusions:

• The 26S proteasome is a novel driver of TNR expansions in both yeast and human cells.
• Protein degradation mediated by the 26S proteasome plays a significant role in TNR expansion processes.
• Targeting the 26S proteasome may offer therapeutic strategies for TNR-expansion-associated neurological diseases.