Huntington's disease (HD) belongs to a family of neurodegenerative diseases caused by misfolded proteins and shares the pathological hallmark of selective accumulation of misfolded proteins in neuronal cells. Polyglutamine expansion in the HD protein, huntingtin (Htt), causes selective neurodegeneration that is more severe in the striatum and cortex than in other brain regions, but the mechanism behind this selectivity is unknown. Here we report that in HD knock-in mice, the expression levels of mutant Htt (mHtt) are higher in brain tissues than in peripheral tissues. However, the expression of N-terminal mHtt via stereotaxic injection of viral vectors in mice also results in greater accumulation of mHtt in the striatum than in muscle. We developed an in vitro assay that revealed that extracts from the striatum and cortex promote the formation of high-molecular weight (HMW) mHtt compared with the relatively unaffected cerebellar and peripheral tissue extracts. Inhibition of ubiquitin-activating enzyme E1 (Ube1) increased the levels of HMW mHtt in the relatively unaffected tissues. Importantly, the expression levels of Ube1 are lower in brain tissues than peripheral tissues and decline in the nuclear fraction with age, which is correlated with the increased accumulation of mHtt in the brain and neuronal nuclei during aging. Our findings suggest that decreased targeting of misfolded Htt to the proteasome for degradation via Ube1 may underlie the preferential accumulation of toxic forms of mHtt in the brain and its selective neurodegeneration.