PUBLICATION

Novel targets for Huntington's disease in an mTOR-independent autophagy pathway

Authors
Williams, A., Sarkar, S., Cuddon, P., Ttofi, E.K., Saiki, S., Siddiqi, F.H., Jahreiss, L., Fleming, A., Pask, D., Goldsmith, P., O'Kane, C.J., Floto, R.A., and Rubinsztein, D.C.
ID
ZDB-PUB-080414-10
Date
2008
Source
Nature Chemical Biology   4(5): 295-305 (Journal)
Registered Authors
Fleming, Angeleen
Keywords
none
MeSH Terms
  • Animals
  • Autophagy/drug effects*
  • Calcium Channels, L-Type/drug effects
  • Clonidine/pharmacology
  • Cyclic AMP/metabolism
  • Humans
  • Huntington Disease/immunology
  • Huntington Disease/physiopathology*
  • Imidazoline Receptors/antagonists & inhibitors
  • Minoxidil/pharmacology
  • Protein Kinases/physiology*
  • Signal Transduction
  • TOR Serine-Threonine Kinases
  • Type C Phospholipases/metabolism
  • Verapamil/pharmacology
PubMed
18391949 Full text @ Nat. Chem. Biol.
Abstract
Autophagy is a major clearance route for intracellular aggregate-prone proteins causing diseases such as Huntington's disease. Autophagy induction with the mTOR inhibitor rapamycin accelerates clearance of these toxic substrates. As rapamycin has nontrivial side effects, we screened FDA-approved drugs to identify new autophagy-inducing pathways. We found that L-type Ca(2+) channel antagonists, the K(+)(ATP) channel opener minoxidil, and the G(i) signaling activator clonidine induce autophagy. These drugs revealed a cyclical mTOR-independent pathway regulating autophagy, in which cAMP regulates IP(3) levels, influencing calpain activity, which completes the cycle by cleaving and activating G(salpha), which regulates cAMP levels. This pathway has numerous potential points where autophagy can be induced, and we provide proof of principle for therapeutic relevance in Huntington's disease using mammalian cell, fly and zebrafish models. Our data also suggest that insults that elevate intracytosolic Ca(2+) (like excitotoxicity) inhibit autophagy, thus retarding clearance of aggregate-prone proteins.
Genes / Markers
Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes