α-Synuclein levels modulate Huntington's disease in mice

Hum Mol Genet. 2012 Feb 1;21(3):485-94. doi: 10.1093/hmg/ddr477. Epub 2011 Oct 18.

Abstract

α-Synuclein and mutant huntingtin are the major constituents of the intracellular aggregates that characterize the pathology of Parkinson's disease (PD) and Huntington's disease (HD), respectively. α-Synuclein is likely to be a major contributor to PD, since overexpression of this protein resulting from genetic triplication is sufficient to cause human forms of PD. We have previously demonstrated that wild-type α-synuclein overexpression impairs macroautophagy in mammalian cells and in transgenic mice. Overexpression of human wild-type α-synuclein in cells and Drosophila models of HD worsens the disease phenotype. Here, we examined whether α-synuclein overexpression also worsens the HD phenotype in a mammalian system using two widely used N-terminal HD mouse models (R6/1 and N171-82Q). We also tested the effects of α-synuclein deletion in the same N-terminal HD mouse models, as well as assessed the effects of α-synuclein deletion on macroautophagy in mouse brains. We show that overexpression of wild-type α-synuclein in both mouse models of HD enhances the onset of tremors and has some influence on the rate of weight loss. On the other hand, α-synuclein deletion in both HD models increases autophagosome numbers and this is associated with a delayed onset of tremors and weight loss, two of the most prominent endophenotypes of the HD-like disease in mice. We have therefore established a functional link between these two aggregate-prone proteins in mammals and provide further support for the model that wild-type α-synuclein negatively regulates autophagy even at physiological levels.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age of Onset
  • Animals
  • Brain / metabolism
  • Disease Models, Animal
  • Disease Progression
  • Female
  • Gene Deletion
  • Humans
  • Huntingtin Protein
  • Huntington Disease / genetics
  • Huntington Disease / metabolism*
  • Huntington Disease / pathology
  • Intranuclear Inclusion Bodies / ultrastructure
  • Male
  • Mice
  • Mice, Transgenic
  • Microtubule-Associated Proteins / metabolism
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Nuclear Proteins / metabolism
  • Tremor / epidemiology
  • Tremor / metabolism
  • Weight Loss
  • alpha-Synuclein / deficiency
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism*

Substances

  • HTT protein, human
  • Htt protein, mouse
  • Huntingtin Protein
  • MAP1LC3 protein, mouse
  • Microtubule-Associated Proteins
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • SNCA protein, human
  • Snca protein, mouse
  • alpha-Synuclein