Aggregate formation inhibits proteasomal degradation of polyglutamine proteins

• Published in: Human molecular genetics 2002-10, Vol.11 (22), p.2689-2700
• Main Authors: Verhoef, Lisette G.G.C., Lindsten, Kristina, Masucci, Maria G., Dantuma, Nico P.
• Format: Article
• Language: English
• Subjects: Ataxin-1; Ataxins; Biodegradation, Environmental; Biological and medical sciences; Cell metabolism, cell oxidation; Cell physiology; Cysteine Endopeptidases - metabolism; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Drug Stability; Fundamental and applied biological sciences. Psychology; Green Fluorescent Proteins; HeLa Cells; Humans; Luminescent Proteins - chemistry; Luminescent Proteins - genetics; Luminescent Proteins - metabolism; Macromolecular Substances; Medical sciences; Medicin och hälsovetenskap; Molecular and cellular biology; Multienzyme Complexes - metabolism; Nerve Tissue Proteins - chemistry; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurology; Nuclear Proteins - chemistry; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Peptides - chemistry; Peptides - genetics; Peptides - metabolism; Proteasome Endopeptidase Complex; Protein Sorting Signals - genetics; Recombinant Fusion Proteins - chemistry; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Repetitive Sequences, Amino Acid; Solubility; Transfection; Ubiquitin - chemistry; Ubiquitin - genetics; Ubiquitin - metabolism
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/11.22.2689

Insoluble protein aggregates are consistently found in neurodegenerative disorders caused by expanded polyglutamine [poly(Q)] repeats. The aggregates contain various components of the ubiquitin/proteasome system, suggesting an attempt of the cell to clear the aberrant substrate. To investigate the effect of expanded poly(Q) repeats on ubiquitin/proteasome-dependent proteolysis, we targeted these proteins for proteasomal degradation by the introduction of an N-end rule degradation signal. While soluble poly(Q) proteins were degraded, they resisted proteasomal degradation once present in the aggregates. Stabilization was also observed for proteins that are co-aggregated via interaction with the expanded poly(Q) domain. Introduction of a degradation signal in ataxin-1/Q92 reduced the incidence of nuclear inclusions and the cellular toxicity, conceivably by accelerating the clearance of the soluble substrate.