Lithium rescues toxicity of aggregate-prone proteins in Drosophila by perturbing Wnt pathway.
We have previously shown that lithium can protect against the polyglutamine toxicity of the Huntington's disease mutation in cell models. Here, we demonstrate for the first time in vivo that lithium can protect against the toxicity caused by aggregate-prone proteins with either polyglutamine or polyalanine expansions in Drosophila. We also show that these protective effects can be partly accounted for by lithium acting through the Wnt/Wg pathway, as a GSK3beta-specific inhibitor and overexpression of dTCF also mediate protective effects. Our data suggest that lithium deserves serious consideration for further studies as a therapeutic for polyglutamine diseases, particularly as it is an established drug that has been used for several decades for chronic treatment of affective disorders.
Berger
Zdenek
Z
Department of Medical Genetics, Cambridge Institute for Medical Research, Addenbrooke's Hospital, UK.
Ttofi
Evangelia K
EK
Michel
Claire H
CH
Pasco
Matthieu Y
MY
Tenant
Sean
S
Rubinsztein
David C
DC
O'Kane
Cahir J
CJ
D000818:Animals; D004330:Drosophila / Q000187:drug effects* / Q000378:metabolism; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008094:Lithium / Q000494:pharmacology* / Q000627:therapeutic use; D010455:Peptides / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000633:toxicity*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics / Q000502:physiology; D051153:Wnt Proteins / Q000378:metabolism*
D029721:Drosophila Proteins; D010455:Peptides; D047428:Protein Kinase Inhibitors; D051153:Wnt Proteins; C097188:polyglutamine; D008094:Lithium; C080335:Sgg protein, Drosophila; D038362:Glycogen Synthase Kinase 3