[Neurodegenerative polyglutamine expansion diseases: physiopathology and therapeutic strategies]

Abstract

Polyglutamine expansion diseases are adult-onset inherited neurodegenerative disorders that lead to death 10 to 20 years after the first symptoms. Currently, there is no therapy to fight against these diseases. They include Huntington's disease, spinobulbar muscular atrophy, dentatorubral-pallido-luysian atrophy and six types of spino-cerebellar ataxia. The diseases are caused by a unique mutational mechanism: an expansion of the CAG trinucleotide in the corresponding genes coding for an expanded tract of glutamine in the mutated proteins. Polyglutamine expansion confers to the mutant proteins toxic properties that cause neuronal cell death in brain regions specific to each disease. Thanks to cellular and animal models (fly, fish, mouse and rat) of these diseases, we have considerably improved our understanding of the toxic nature of polyglutamine expansion and the physiopathology, and we are now in position to design and test therapeutic strategies to prevent or delay the disease process.