In Huntington's disease (HD) brains and other tissues, UPS activity is inhibited and intraneuronal nuclear protein aggregates of mutant huntingtin in HD brains indicate dysfunction of the UPS. From these results, we hypothesized that enhancing UPS function would improve catalytic degradation of abnormal proteins in HD. We first genetically engineered proteasome activators involved in either non-ubiquitinated protein degradation pathways (PA28ƒ×) or subunits of PA700, the 26S proteasome ubiquitinated pathway (S5a) into transducible lentiviral vectors. To address the therapeutic hypothesis experimentally, we transduced UPS subunits into HD skin fibroblasts or HD mutant protein expressing striatum-derived neurons. We determined how this intervention altered cell survival after exposure to toxins known to simulate pathological mechanisms in HD.
The manuscript shows that cellular changes due to expression of huntingtin protein with longer CAG repeats can reduce the ubiquitin proteasome system (UPS) function in Huntington¡¦s disease cells. Following compromise of the UPS, the overexpression of proteasome activator PA28 can specifically recover proteasome function and improve cell viability in both HD model and patient cells.
These remarkable results demonstrat e for the first time that it is possible to intervene therapeutically in the proteolytic pathways and organelles that participate in the specific degradation of misfolded and abnormal proteins.