PMID- 17921520
OWN - NLM
STAT- MEDLINE
DCOM- 20080229
LR  - 20220129
IS  - 1460-2083 (Electronic)
IS  - 0964-6906 (Linking)
VI  - 17
IP  - 2
DP  - 2008 Jan 15
TI  - A rational mechanism for combination treatment of Huntington's disease using 
      lithium and rapamycin.
PG  - 170-8
AB  - Huntington's disease (HD) is caused by a polyglutamine expansion mutation in the 
      huntingtin protein that confers a toxic gain-of-function and causes the protein 
      to become aggregate-prone. Aggregate-prone proteins are cleared by 
      macroautophagy, and upregulating this process by rapamycin, which inhibits the 
      mammalian target of rapamycin (mTOR), attenuates their toxicity in various HD 
      models. Recently, we demonstrated that lithium induces mTOR-independent autophagy 
      by inhibiting inositol monophosphatase (IMPase) and reducing inositol and IP3 
      levels. Here we show that glycogen synthase kinase-3beta (GSK-3beta), another 
      enzyme inhibited by lithium, has opposite effects. In contrast to IMPase 
      inhibition that enhances autophagy, GSK3beta inhibition attenuates autophagy and 
      mutant huntingtin clearance by activating mTOR. In order to counteract the 
      autophagy inhibitory effects of mTOR activation resulting from lithium treatment, 
      we have used the mTOR inhibitor rapamycin in combination with lithium. This 
      combination enhances macroautophagy by mTOR-independent (IMPase inhibition by 
      lithium) and mTOR-dependent (mTOR inhibition by rapamycin) pathways. We provide 
      proof-of-principle for this rational combination treatment approach in vivo by 
      showing greater protection against neurodegeneration in an HD fly model with TOR 
      inhibition and lithium, or in HD flies treated with rapamycin and lithium, 
      compared with either pathway alone.
FAU - Sarkar, Sovan
AU  - Sarkar S
AD  - Department of Medical Genetics, University of Cambridge, Cambridge Institute for 
      Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.
FAU - Krishna, Gauri
AU  - Krishna G
FAU - Imarisio, Sara
AU  - Imarisio S
FAU - Saiki, Shinji
AU  - Saiki S
FAU - O'Kane, Cahir J
AU  - O'Kane CJ
FAU - Rubinsztein, David C
AU  - Rubinsztein DC
LA  - eng
GR  - 064354/WT_/Wellcome Trust/United Kingdom
GR  - G0600194/MRC_/Medical Research Council/United Kingdom
GR  - G0600194(77639)/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20071006
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (Drosophila Proteins)
RN  - 0 (Lithium Compounds)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 4L6452S749 (Inositol)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.- (target of rapamycin protein, Drosophila)
RN  - EC 2.7.11.1 (GSK3B protein, human)
RN  - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta)
RN  - EC 2.7.11.1 (Gsk3b protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.26 (Glycogen Synthase Kinase 3)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Autophagy/*drug effects
MH  - COS Cells
MH  - Chlorocebus aethiops
MH  - Disease Models, Animal
MH  - *Drosophila
MH  - Drosophila Proteins/antagonists & inhibitors
MH  - Female
MH  - Glycogen Synthase Kinase 3/antagonists & inhibitors
MH  - Glycogen Synthase Kinase 3 beta
MH  - Humans
MH  - Huntington Disease/*drug therapy
MH  - Inositol/biosynthesis
MH  - Lithium Compounds/*pharmacology/therapeutic use
MH  - Male
MH  - Mice
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Protein Kinases
MH  - Sirolimus/*pharmacology/therapeutic use
MH  - TOR Serine-Threonine Kinases
EDAT- 2007/10/09 09:00
MHDA- 2008/03/01 09:00
CRDT- 2007/10/09 09:00
PHST- 2007/10/09 09:00 [pubmed]
PHST- 2008/03/01 09:00 [medline]
PHST- 2007/10/09 09:00 [entrez]
AID - ddm294 [pii]
AID - 10.1093/hmg/ddm294 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2008 Jan 15;17(2):170-8. doi: 10.1093/hmg/ddm294. Epub 2007 Oct 6.