α-Synuclein levels modulate Huntington's disease in mice.

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.

• Authors: Silvia Corrochano, Maurizio Renna, Sarah Carter, Nichola Chrobot, Rose Kent, Michelle Stewart, Jason Cooper, Steve D M Brown, David C Rubinsztein, Abraham Acevedo-Arozena
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 21 Issue 3 Pg. 485-94 (Feb 01 2012) ISSN: 1460-2083 [Electronic] England
• PMID: 22010050 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• HTT protein, human
• Htt protein, mouse
• Huntingtin Protein
• Map1lc3b protein, mouse
• Microtubule-Associated Proteins
• Nerve Tissue Proteins
• Nuclear Proteins
• SNCA protein, human
• Snca protein, mouse
• alpha-Synuclein

Topics

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