Phenylbutyric acid suppresses protein accumulation-mediated ER stress in retrovirus-infected astrocytes and delays onset of paralysis in infected mice.

Many neurodegenerative diseases are associated with accumulation of misfolded proteins in cells of the central nervous system (CNS). We have previously reported that accumulation of the precursor envelope protein gPr80(env) of ts1, a mutant of Moloney murine leukemia virus (MoMuLV), in the endoplasmic reticulum (ER) of infected astrocytes, results in ER stress, oxidative stress and cell death, subsequently leading to ts1-mediated neurodegeneration in infected mice. In the present study, we assessed whether treatments that reduce the accumulation of gPr80(env) in the ER of ts1-infected astrocytes provided a protective effect against ER stress and cell death. We show that treatment with phenylbutyric acid (PBA) can prevent the unfolded protein response (UPR), ER stress and cell death in cultured ts1-infected astrocytes. The protective effect of PBA is associated with its ability to reduce gPr80(env) accumulation and to increase the expression of proteins involved in protein folding in the ER, such as protein disulfide isomerase (PDI) and ERp44, rather than by decrease mRNA levels of gPr80(env) or alter the proteasomal degradation process for gPr80(env). In infected mice treated with PBA we also noted a reduction in the severity of the neuropathology in brainstem tissues and a delayed onset of paralysis. These results show that PBA is a potentially effective drug for the treatment of neurodegeneration caused by protein accumulation in cells of the CNS.