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

Nat Chem Biol. 2008 May;4(5):295-305. doi: 10.1038/nchembio.79.


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 Ca2+ 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 IP3 levels, influencing calpain activity, which completes the cycle by cleaving and activating G(s)alpha, 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 Ca2+ (like excitotoxicity) inhibit autophagy, thus retarding clearance of aggregate-prone proteins.

Publication types

  • Research Support, Non-U.S. Gov't

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


  • Calcium Channels, L-Type
  • Imidazoline Receptors
  • imidazoline I1 receptors
  • Minoxidil
  • Verapamil
  • Cyclic AMP
  • Protein Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Type C Phospholipases
  • Clonidine