Deletion of the huntingtin polyglutamine stretch enhances neuronal autophagy and longevity in mice

PLoS Genet. 2010 Feb 5;6(2):e1000838. doi: 10.1371/journal.pgen.1000838.


Expansion of a stretch of polyglutamine in huntingtin (htt), the protein product of the IT15 gene, causes Huntington's disease (HD). Previous investigations into the role of the polyglutamine stretch (polyQ) in htt function have suggested that its length may modulate a normal htt function involved in regulating energy homeostasis. Here we show that expression of full-length htt lacking its polyglutamine stretch (DeltaQ-htt) in a knockin mouse model for HD (Hdh(140Q/DeltaQ)), reduces significantly neuropil mutant htt aggregates, ameliorates motor/behavioral deficits, and extends lifespan in comparison to the HD model mice (Hdh(140Q/+)). The rescue of HD model phenotypes is accompanied by the normalization of lipofuscin levels in the brain and an increase in the steady-state levels of the mammalian autophagy marker microtubule-associate protein 1 light chain 3-II (LC3-II). We also find that DeltaQ-htt expression in vitro increases autophagosome synthesis and stimulates the Atg5-dependent clearance of truncated N-terminal htt aggregates. DeltaQ-htt's effect on autophagy most likely represents a gain-of-function, as overexpression of full-length wild-type htt in vitro does not increase autophagosome synthesis. Moreover, Hdh(DeltaQ/DeltaQ) mice live significantly longer than wild-type mice, suggesting that autophagy upregulation may be beneficial both in diseases caused by toxic intracellular aggregate-prone proteins and also as a lifespan extender in normal mammals.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy*
  • Autophagy-Related Protein 5
  • Behavior, Animal
  • Cell Line
  • Disease Models, Animal
  • Humans
  • Huntingtin Protein
  • Huntington Disease / metabolism
  • Huntington Disease / pathology
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Lipofuscin / metabolism
  • Longevity*
  • Mice
  • Microtubule-Associated Proteins / metabolism
  • Motor Activity
  • Neostriatum / metabolism
  • Neostriatum / pathology
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Neurons / pathology*
  • Neuropil / metabolism
  • Neuropil / pathology
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Peptides / genetics*
  • Phagosomes / metabolism
  • Protein Serine-Threonine Kinases / metabolism
  • Protein Structure, Quaternary
  • Sequence Deletion / genetics*
  • Signal Transduction
  • TOR Serine-Threonine Kinases


  • Atg5 protein, mouse
  • Autophagy-Related Protein 5
  • Htt protein, mouse
  • Huntingtin Protein
  • Intracellular Signaling Peptides and Proteins
  • Lipofuscin
  • Map1lc3b protein, mouse
  • Microtubule-Associated Proteins
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Peptides
  • polyglutamine
  • MTOR protein, human
  • mTOR protein, mouse
  • Protein Serine-Threonine Kinases
  • TOR Serine-Threonine Kinases