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.
Citation
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. (2008) Novel targets for Huntington's disease in an mTOR-independent autophagy pathway. Nature Chemical Biology. 4(5):295-305.
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
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping