Inhibition of Polyglutamine Aggregation in R6/2 HD Brain Slices—Complex Dose–Response Profiles

• Published in: Neurobiology of disease 2001-12, Vol.8 (6), p.1017-1026
• Main Authors: Smith, Donna L., Portier, Ruben, Woodman, Ben, Hockly, Emma, Mahal, Amarbirpal, Klunk, William E., Li, Xiao-Jiang, Wanker, Erich, Murray, Karl D., Bates, Gillian P.
• Format: Article
• Language: English
• Subjects: Animals; Benzoates - pharmacology; Biphenyl Compounds - pharmacology; Cells, Cultured; Coloring Agents - pharmacology; Congo Red - pharmacology; Creatine - pharmacology; Cysteine Endopeptidases - drug effects; Cysteine Endopeptidases - metabolism; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Energy Metabolism - drug effects; Energy Metabolism - physiology; Female; Hippocampus - drug effects; Hippocampus - metabolism; Hippocampus - pathology; Huntington Disease - drug therapy; Huntington Disease - genetics; Huntington Disease - metabolism; Immunohistochemistry; Male; Mice; Mice, Transgenic; Multienzyme Complexes - drug effects; Multienzyme Complexes - metabolism; Nerve Tissue Proteins - drug effects; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Neuroprotective Agents - pharmacology; Nuclear Proteins - drug effects; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Organ Culture Techniques; Peptides - drug effects; Peptides - genetics; Peptides - metabolism; Proteasome Endopeptidase Complex; Protein Folding; Trinucleotide Repeat Expansion - drug effects; Trinucleotide Repeat Expansion - genetics; Ubiquitin - drug effects; Ubiquitin - genetics; Ubiquitin - metabolism
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1006/nbdi.2001.0438

Huntington's disease (HD) is a late onset neurodegenerative disorder caused by a CAG/polyglutamine (polyQ) repeat expansion. PolyQ aggregates can be detected in the nuclei and processes of neurons in HD patients and mouse models prior to the onset of symptoms. The misfolding and aggregation pathway is an important therapeutic target. To better test the efficacy of aggregation inhibitors, we have developed an organotypic slice culture system. We show here that the formation of polyQ aggregates in hippocampal slices established from the R6/2 mouse follows the same prescribed sequence as occurs in vivo. Using this assay, we show that Congo red and chrysamine G can modulate aggregate formation, but show complex dose–response curves. Oral administration of creatine has been shown to delay the onset of all aspects of the phenotype and neuropathology in R6/2 mice. We show here that creatine can similarly inhibit aggregate formation in the slice culture assay.