UPR Responsive Genes Manf and Xbp1 in Stroke

Abstract

Stroke is a devastating medical condition with no treatment to hasten recovery. Its abrupt nature results in cataclysmic changes in the affected tissues. Resident cells fail to cope with the cellular stress resulting in massive cell death, which cannot be endogenously repaired. A potential strategy to improve stroke outcomes is to boost endogenous pro-survival pathways. The unfolded protein response (UPR), an evolutionarily conserved stress response, provides a promising opportunity to ameliorate the survival of stressed cells. Recent studies from us and others have pointed toward mesencephalic astrocyte-derived neurotrophic factor (MANF) being a UPR responsive gene with an active role in maintaining proteostasis. Its pro-survival effects have been demonstrated in several disease models such as diabetes, neurodegeneration, and stroke. MANF has an ER-signal peptide and an ER-retention signal; it is secreted by ER calcium depletion and exits cells upon cell death. Although its functions remain elusive, conducted experiments suggest that the endogenous MANF in the ER lumen and exogenously administered MANF protein have different mechanisms of action. Here, we will revisit recent and older bodies of literature aiming to delineate the expression profile of MANF. We will focus on its neuroprotective roles in regulating neurogenesis and inflammation upon post-stroke administration. At the same time, we will investigate commonalities and differences with another UPR responsive gene, X-box binding protein 1 (XBP1), which has recently been associated with MANF’s function. This will be the first systematic comparison of these two UPR responsive genes aiming at revealing previously uncovered associations between them. Overall, understanding the mode of action of these UPR responsive genes could provide novel approaches to promote cell survival.

Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF): An Emerging Therapeutic Target for Neurodegenerative Disorders

“…Other proteins with CXXC motifs found abundantly in the ER include protein disulfide isomerase (PDI) and reductase [ 17 ]. However, MANF does not show any PDI activity [ 18 ]. Strikingly, a mutation in the CXXC motif was shown to abolish MANF’s neuroprotective property.…”

“…Stroke is one of the leading causes of disability in humans worldwide [ 18 ]. It is caused by local thrombosis or hemorrhage, leading to a lack of blood supply to the corresponding brain region, resulting in neuron death [ 52 ].…”

Reevaluating the Concept of Aging: Long-Term Stress Adaptation as a Key Factor in Yeast Aging

“…In quiescent cells, xbp1 transcripts are the most abundant and have the capability to repress around 15% of all yeast genes as the cells transition into the quiescent state. It is also important Numerous studies in higher eukaryotes have revealed the induction or detection of xbp1 expression in various types of cancer cells 67 , as well as in conditions such as stroke 68 and neurodegenerative diseases, including Alzheimer's disease 69 . The overexpression of xbp1 has demonstrated certain advantageous effects in the aging of the mammalian brain 69,70 .…”

CDNF and MANF in the brain dopamine system and their potential as treatment for Parkinson’s disease

“…CDNF is a vertebrate-specific paralog of MANF (12). In cells, CDNF and MANF localize in the endoplasmic reticulum (ER) (19,20), where they regulate protein homeostasis and ER stress-induced unfolded protein response (UPR) signaling (21)(22)(23)(24)(25). As a potential therapeutic factor for dopamine neurons, CDNF was tested in Phase I-II clinical trials in 17 PD patients, where it was shown to be safe and well tolerated (26,27).…”