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M12 A769662 Leads to AMPK Activation, Induces Autophagy and has Beneficial Effects IN HD Cells
  1. C Walter1,
  2. S Metzger1,
  3. A Weiss2,3,
  4. O Riess1,
  5. H Phuc Nguyen1
  1. 1Department of Medical Genetics, University of Tuebingen, Tuebingen, Germany
  2. 2Novartis Institutes for Biomedical Research, Novartis Campus, Basel, Switzerland
  3. 3Present Address: IRBM Promidis, Pomezia, Italy

Abstract

Background The expansion of a polyglutamine repeat in the HD gene encoding huntingtin (htt) protein causes Huntington disease (HD). Although the exact pathogenesis is not known in its entirety, mutant htt causes disruption of various cellular functions, formation of aggregates and finally cell death. The process of autophagy is the main degradation pathway for mutant htt and various studies demonstrated that the induction of autophagy leads to an improvement of aggregate formation and cell viability. Commonly, the mTor inhibitor rapamycin is used for autophagy induction and has been shown to protect against mutant htt mediated toxicity in several HD models.

Aim/method As rapamycin, beside autophagy induction, also suppresses mTor mediated protein synthesis, we aimed to characterise AMPK as a new drug target for autophagy induction. In this regard, we analysed AMPK activation by the AMPK inducer A769662 and its effects on autophagic degradation and mutant htt mediated toxicity.

Results Activation of AMPK by A769662 led to an increased expression of the autophagosomal markers LC3 and p62, suggesting an efficient induction of autophagy. The autophagy induction is accompanied by a decrease of mutant htt expression and cytotoxicity. Additionally, mTor mediated protein synthesis, measured by the S6K1 (ribosomal protein S6 kinase) and RPS6 (ribosomal protein S6) expression is not affected.

Conclusion Therefore, we identified AMPK as an interesting therapeutic target and A769662 as a potential treatment compound to facilitate the clearance of mutant htt without interfering with mTor mediated protein synthesis.

KeyWords
  • huntington disease
  • autophagy
  • AMPK
  • A769662

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