Rescue of ATXN3 neuronal toxicity in by chemical modification of endoplasmic reticulum stress.

Polyglutamine expansion diseases are a group of hereditary neurodegenerative disorders that develop when a CAG repeat in the causative genes is unstably expanded above a certain threshold. The expansion of trinucleotide CAG repeats causes hereditary adult-onset neurodegenerative disorders, such as Huntington's disease, dentatorubral-pallidoluysian atrophy, spinobulbar muscular atrophy and multiple forms of spinocerebellar ataxia (SCA). The most common dominantly inherited SCA is the type 3 (SCA3), also known as Machado-Joseph disease (MJD), which is an autosomal dominant, progressive neurological disorder. The gene causatively associated with MJD is Recent studies have shown that this gene modulates endoplasmic reticulum (ER) stress. We generated transgenic strains expressing human genes in motoneurons, and animals expressing mutant alleles showed decreased lifespan, impaired movement, and rates of neurodegeneration greater than wild-type controls. We tested three neuroprotective compounds (Methylene Blue, guanabenz and salubrinal) believed to modulate ER stress and observed that these molecules rescued phenotypes. Furthermore, these compounds required specific branches of the ER unfolded protein response (UPR), reduced global ER and oxidative stress, and polyglutamine aggregation. We introduce new models for MJD based on the expression of full-length in a limited number of neurons. Using these models, we discovered that chemical modulation of the UPR reduced neurodegeneration and warrants investigation in mammalian models of MJD.