Differential activities of the ubiquitin-proteasome system in neurons versus glia may account for the preferential accumulation of misfolded proteins in neurons.

A variety of neurological disorders and polyglutamine (polyQ) diseases are caused by misfolded proteins. The common feature of these diseases is late-onset cellular degeneration that selectively affects neurons in distinct brain regions. polyQ diseases, including Huntington's disease (HD), present a clear case of selective neurodegeneration caused by polyQ expansion-induced protein misfolding, which also leads to predominant inclusions in neuronal nuclei. It remains unclear how these ubiquitously expressed disease proteins selectively kill neurons. In HD, mutant huntingtin accumulates in both neurons and glia, but more neuronal cells display huntingtin aggregates. These aggregates colocalize with components of the ubiquitin-proteasome system (UPS), which plays a critical role in clearing misfolded proteins. Using fluorescent reporters that reflect cellular UPS activity, we found that UPS activity in cultured neurons and glia decreases in a time-dependent manner. Importantly, UPS activity is lower in neurons than in glia and also lower in the nucleus than the cytoplasm. By expressing the UPS reporters in glia and neurons in the mouse brain, we also observed an age-dependent decrease in UPS activity, which is more pronounced in neurons than glial cells. Although brain UPS activities were similar between wild-type and HD 150Q knock-in mice, inhibiting the UPS markedly increases the accumulation of mutant htt in cultured glial cells. These findings suggest that the lower neuronal UPS activity may account for the preferential accumulation of misfolded proteins in neurons, as well as their selective vulnerability.