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 gPr80env 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 gPr80env 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 gPr80env 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 gPr80env or alter the proteasomal degradation process for gPr80env. 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.

Research highlights▶ PBA reduces gPr80env accumulation and increases the levels of ER folding proteins PDI and ERp44. ▶ PBA do not affect mRNA levels of gPr80env or alter the proteasomal degradation process for gPr80env. ▶ PBA prevents the UPR, ER stress and cell death in ts1-infected astrocytes. ▶ PBA reduces the severity of the neuropathology and delays onset of paralysis in infected mice. ▶ PBA may be an effective drug to treat misfolded protein accumulation related neurodegeneration.