A potent small molecule inhibits polyglutamine aggregation in Huntington's disease neurons and suppresses neurodegeneration in vivo.
Polyglutamine (polyQ) disorders, including Huntington's disease (HD), are caused by expansion of polyQ-encoding repeats within otherwise unrelated gene products. In polyQ diseases, the pathology and death of affected neurons are associated with the accumulation of mutant proteins in insoluble aggregates. Several studies implicate polyQ-dependent aggregation as a cause of neurodegeneration in HD, suggesting that inhibition of neuronal polyQ aggregation may be therapeutic in HD patients. We have used a yeast-based high-throughput screening assay to identify small-molecule inhibitors of polyQ aggregation. We validated the effects of four hit compounds in mammalian cell-based models of HD, optimized compound structures for potency, and then tested them in vitro in cultured brain slices from HD transgenic mice. These efforts identified a potent compound (IC50=10 nM) with long-term inhibitory effects on polyQ aggregation in HD neurons. Testing of this compound in a Drosophila HD model showed that it suppresses neurodegeneration in vivo, strongly suggesting an essential role for polyQ aggregation in HD pathology. The aggregation inhibitors identified in this screen represent four primary chemical scaffolds and are strong lead compounds for the development of therapeutics for human polyQ diseases.
Zhang
Xiaoqian
X
Department of Biochemistry, Boston University Medical School, Boston, MA 02118, USA.
Smith
Donna L
DL
Meriin
Anatoli B
AB
Engemann
Sabine
S
Russel
Deborah E
DE
Roark
Margo
M
Washington
Shetia L
SL
Maxwell
Michele M
MM
Marsh
J Lawrence
JL
Thompson
Leslie Michels
LM
Wanker
Erich E
EE
Young
Anne B
AB
Housman
David E
DE
Bates
Gillian P
GP
Sherman
Michael Y
MY
Kazantsev
Aleksey G
AG
D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000473:pathology; D019281:Dimerization; D004195:Disease Models, Animal; D004330:Drosophila; D006816:Huntington Disease / Q000378:metabolism / Q000473:pathology*; D020128:Inhibitory Concentration 50; D051379:Mice; D008822:Mice, Transgenic; D019636:Neurodegenerative Diseases / Q000517:prevention & control*; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D010455:Peptides / Q000037:antagonists & inhibitors*; D011084:Polycyclic Aromatic Hydrocarbons / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000494:pharmacology*
D000813:Anilides; C524875:N-(4-bromophenyl) 3-(4-bromophenylaminosulfonyl)benzamide; D010455:Peptides; D011084:Polycyclic Aromatic Hydrocarbons; D013449:Sulfonamides; C097188:polyglutamine