Together with the decrease in the level of plasma triglycerides, suggests that the external glucose load might trigger a switch from the use of fatty acids as fuel in fasted fish to the use of glucose as fuel in glucose treated fish. In this work we characterize the effects of mutant ataxin-3 silencing on MJDassociated motor behavior and neuropathological abnormalities in a pre-symptomatic cerebellar mouse model by co-injecting lentiviral vectors encoding for the silencing short hairpins RNAs and vectors encoding for mutant ataxin-3. We show that early mutant ataxin-3 silencing abolishes the appearance of balance and motor coordination deficits, ataxic gait and histological hallmarks of the disease. MJD belongs to a wide group of similar disorders designated polyglutamine diseases. MJD is characterized by diverse clinical presentation, particularly cerebellar ataxia, along with other symptoms such as peripheral neuropathy, bulging eyes, ophthalmoplegia, dystonia, nystagmus and fasciculations. A abnormally misfolded protein, typically in the form of intranuclear neuronal inclusions in affected brain regions, such as afferent and efferent cerebellar systems, substantia nigra, cranial nerve motor nuclei and striatum. MJD is the most common ataxia worldwide and similarly to most other polyglutamine diseases no treatment is available. In the last years, the strategy of gene silencing by RNA interference has been proposed to knock-down the expression of mutant genes in order to rescue the phenotype of dominant disorders, including polyglutamine diseases. Other strategies have been proposed to improve mutant protein clearance and mitigate its toxic effects, but within the molecular cascade that leads ultimately to neuronal dysfunction and cell death, none of these acts as early as RNA interference, which we and others have shown to be effective to treat several diseases including MJD. However, for the specific case of MJD, in vivo studies testing the ability of gene silencing initiated at an early stage to prevent the appearance and progression of motor behavior abnormalities were missing. This is particularly relevant in MJD as patient’s genotyping could allow initiation of treatment before the appearance of the first symptoms. The lentiviral mouse model here used is particularly suited for this specific study as it allows initiation of the knock-down of mutant ataxin-3 at an early time-point before onset of symptoms. One important issue to Regorafenib consider is whether allele-specific silencing of mutant ataxin-3 or generalized silencing of both alleles of the protein, wild-type and expanded/mutant should be done. The ataxin-3 protein has a de-ubiquitinating enzyme activity and it has also been linked to aggresome formation, endoplasmatic reticulum-associated degradation, cytoskeleton network, among other roles. Therefore, although knock-out mice for ataxin-3 have no major abnormalities and generalized silencing of ataxin-3 in the context of MJD has proved to be safe and effective, here we used the more cautious approach of allele-specific silencing for the mutant ataxin3. This strategy takes advantage of a single nucleotide polymorphism, which can discriminate the mutant allele in approximately 70% of MJD patients.