A novel action of histone deacetylase inhibitors in a protein aggresome disease model.
Protein inclusions are associated with a number of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Whether protein aggregates are toxic or beneficial to cells is not known. In ALS animal models, mutant SOD1 forms aggresome-like structures in motor neurons and astrocytes. To better understand the role of protein aggregation in the progression of disease etiology, we performed a screen for small molecules that disrupt aggresome formation in cultured cells. After screening 20,000 compounds, we obtained two groups of compounds that specifically prevented aggresome formation. One group consists mainly of cardiac glycosides and will be the subject of another study. The second group contains two compounds: one is a known histone deacetylase (HDAC) inhibitor, Scriptaid, and the other is a Flavin analog, DPD. Cells treated with these molecules still contained microaggregates, but these microaggregates were not transported to microtubule organizing centers (MTOCs). The defect in transport was linked to modulation of the dynein/dynactin machinery as treatment with Scriptaid or DPD reversed mSOD-induced insolubilization of the dynactin subunits P50 dynamitin and P150(glued). Our findings suggest a connection between HDAC activity and aggresome formation and also lay the groundwork for a direct test of the role of aggresome formation in ALS etiology.
Corcoran
Lisa J
LJ
Institute of Chemistry and Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Mitchison
Timothy J
TJ
Liu
Qing
Q
D000690:Amyotrophic Lateral Sclerosis; D000818:Animals; D019556:COS Cells; D002458:Cell Fractionation; D002522:Chlorocebus aethiops; D017931:DNA Primers; D004195:Disease Models, Animal; D000072159:Dynactin Complex; D049452:Green Fluorescent Proteins; D056572:Histone Deacetylase Inhibitors; D006898:Hydroxylamines / Q000494:pharmacology*; D015151:Immunoblotting; D002479:Inclusion Bodies / Q000378:metabolism*; D008164:Luminescent Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D022101:Microtubule-Organizing Center / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
D017931:DNA Primers; D000072159:Dynactin Complex; D056572:Histone Deacetylase Inhibitors; D006898:Hydroxylamines; D008164:Luminescent Proteins; D008869:Microtubule-Associated Proteins; D011804:Quinolines; C410733:scriptaid; D049452:Green Fluorescent Proteins; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1