α-Synuclein levels modulate Huntington's disease in mice.
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.
MRC Mammalian Genetics Unit, Harwell, Oxfordshire OX11 0RD, UK.
Silvia
S
Corrochano
Maurizio
M
Renna
Sarah
S
Carter
Nichola
N
Chrobot
Rose
R
Kent
Michelle
M
Stewart
Jason
J
Cooper
Steve D M
SD
Brown
David C
DC
Rubinsztein
Abraham
A
Acevedo-Arozena
D017668:Age of Onset; D000818:Animals; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D017353:Gene Deletion; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045586:Intranuclear Inclusion Bodies / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D014202:Tremor / Q000453:epidemiology / Q000378:metabolism; D015431:Weight Loss; D051844:alpha-Synuclein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C497604:SNCA protein, human; C497605:Snca protein, mouse; D051844:alpha-Synuclein