Aggregation and proteasome: The case of elongated polyglutamine aggregation in spinal and bulbar muscular atrophy

• Published in: Neurobiology of aging Vol. 28; no. 7; pp. 1099 - 1111
• Main Authors: Rusmini, Paola, Sau, Daniela, Crippa, Valeria, Palazzolo, Isabella, Simonini, Francesca, Onesto, Elisa, Martini, Luciano, Poletti, Angelo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-07-2007
• Subjects: Aggregation; Androgen receptor; Animals; Antiandrogen; Cell Line, Transformed; Humans; Inclusion; Internal Medicine; Luminescent Proteins - genetics; Luminescent Proteins - metabolism; Mice; Motor neuron diseases; Motor Neurons - drug effects; Motor Neurons - metabolism; Muscular Atrophy, Spinal - genetics; Mutation; Neurodegeneration; Neurology; Peptides - genetics; Peptides - metabolism; Polyglutamine diseases; Proteasome; Proteasome Endopeptidase Complex - metabolism; Protein Transport - drug effects; Protein Transport - genetics; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Reverse Transcriptase Polymerase Chain Reaction - methods; RNA, Messenger - biosynthesis; Spinal and bulbar muscular atrophy; Testosterone; Testosterone - pharmacology; Transfection - methods; Trinucleotide Repeat Expansion - genetics; Ubiquitin-Protein Ligase Complexes; Aggregation; Spinal and bulbar muscular atrophy; Testosterone; Inclusion; Motor neuron diseases; Neurodegeneration; Androgen receptor; Antiandrogen; Polyglutamine diseases; Proteasome
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2006.05.015

Abstract Aggregates, a hallmark of most neurodegenerative diseases, may have different properties, and possibly different roles in neurodegeneration. We analysed ubiquitin-proteasome pathway functions during cytoplasmic aggregation in polyglutamine (polyQ) diseases, using a unique model of motor neuron disease, the SpinoBulbar Muscular Atrophy. The disease, which is linked to a polyQ tract elongation in the androgen receptor (ARpolyQ), has the interesting feature that ARpolyQ aggregation is triggered by the AR ligand, testosterone. Using immortalized motor neurons expressing ARpolyQ, we found that a proteasome reporter, YFPu, accumulated in absence of aggregates; testosterone treatment, which induced ARpolyQ aggregation, allowed the normal clearance of YFPu, suggesting that aggregation contributed to proteasome de-saturation, an effect not related to AR nuclear translocation. Using AR antagonists to modulate the kinetic of ARpolyQ aggregation, we demonstrated that aggregation, by removing the neurotoxic protein from the soluble compartment, protected the proteasome from an excess of misfolded protein to be processed.