Overexpression of yeast hsp104 reduces polyglutamine aggregation and prolongs survival of a transgenic mouse model of Huntington's disease

• Published in: Human molecular genetics Vol. 14; no. 22; pp. 3425 - 3433
• Main Authors: Vacher, Coralie, Garcia-Oroz, Lourdes, Rubinsztein, David C.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 15.11.2005; Oxford Publishing Limited (England)
• Subjects: Animals; Biological and medical sciences; Brain - metabolism; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; Heat-Shock Proteins - genetics; Heat-Shock Proteins - physiology; Humans; Huntingtin Protein; Huntington Disease - genetics; Huntington Disease - metabolism; Huntington Disease - mortality; Medical sciences; Mice; Mice, Transgenic; Molecular and cellular biology; Motor Activity - genetics; Nerve Tissue Proteins - metabolism; Neurology; Nuclear Proteins - metabolism; Peptides - antagonists & inhibitors; Peptides - metabolism; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - physiology; Weight Loss - genetics; Animal model; Nervous system diseases; Yeast; Rodentia; Huntington disease; Transgenic animal; Gene overexpression; Survival; Cerebral disorder; Genetic disease; Aggregation; Vertebrata; Mammalia; Mouse; Central nervous system disease; Genetics; Degenerative disease; Extrapyramidal syndrome
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddi372

Huntington's disease is a devastating neurodegenerative condition associated with the formation of intraneuronal aggregates by mutant huntingtin. Aggregate formation is a property shared by the nine related diseases caused by polyglutamine codon expansion mutations and also by other neurodegenerative conditions like Parkinsons's disease. The roles of aggregates and aggregation in these diseases have been a subject of heated controversy. Here, we have addressed the question in vivo by generating a new transgenic mouse overexpressing the yeast chaperone hsp104, as hsp104 overexpression reduced mutant huntingtin aggregation and toxicity in cell models. Hsp104 has no close mammalian orthologues and does not appear to have effects on mammalian cell death pathways. We crossed hsp104 transgenic mice with mice expressing the first 171 residues of mutant huntingtin. Hsp104 reduced aggregate formation and prolonged the lifespan of the HD mice by 20%. This protection may be mediated at the level of changing the conformation of a putative toxic monomer, reducing oligomerization or aggregation, reducing the levels of oligomeric species or aggregates or combinations of these non-mutually exclusive possibilities.