_-Synuclein levels modulate Huntington's disease in mice-

Authors
S. Corrochano, M. Renna, S. Carter, N. Chrobot, R. Kent et al.

Lab
MRC Mammalian Genetics Unit, Harwell, Oxfordshire, UK.

Journal
Human Molecular genetics

Abstract
_-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. _-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 _-synuclein overexpression impairs macroautophagy in mammalian cells and in transgenic mice. Overexpression of human wild-type _-synuclein in cells and Drosophila models of HD worsens the disease phenotype. Here, we examined whether _-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 _-synuclein deletion in the same N-terminal HD mouse models, as well as assessed the effects of _-synuclein deletion on macroautophagy in mouse brains. We show that overexpression of wild-type _-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, _-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 _-synuclein negatively regulates autophagy even at physiological levels.

BIOSEB Instruments Used:
Grip strength test (BIO-GS3)