Mesencephalic Astrocyte-Derived Neurotrophic Factor, or MANF, is an ERS protein which is present in humans and other mammals. Originally thought to be a secreted trophic factor for dopamine neurons in vitro, studies have shown that MANF effectively restores damaged cells in rodents. With research concluding that MANF can successfully restore cells damaged by heart and brain ischemia, Parkinson’s disease, retina in vivo and spinocerebellar ataxia, there is potential for further studies to be conducted in humans.
To date, studies have suggested that the mechanism of action associated with Mesencephalic Astrocyte-Derived Neurotrophic Factor is dependent on its function in alleviating ER stress. As well as having MANF neuroprotective actions selective for dopamine neurons in culture, the protein has been shown to regulate endoplasmic reticulum (ER) stress. Currently, it is believed that its mechanism of action is dependent on its role in alleviating this stress. However, scientists report that the mechanism of Mesencephalic Astrocyte-Derived Neurotrophic Factor has not yet been fully established and is not, therefore, fully understood. With further studies required, it is hoped that the mechanism associated with MANF will be universally established in due course.
ER stress is associated with an array of medical conditions, diseases, and disorders. In order to prevent, limit or reduce these medical issues, ER stress must be regulated. Essentially, Mesencephalic Astrocyte-Derived Neurotrophic Factor works to regulate ER stress and protect cells from damage.
Also known as Arginine-rich, mutated in early-stage tumors (ARMET), MANF inhibits cell replication and can, therefore, prevent the spread of diseases within the body. Furthermore, Mesencephalic Astrocyte-Derived Neurotrophic Factor can protect cells and prevent cell death caused by unregulated ER stress.
Analysis of the structure of MANF has shown two domain proteins with a N-terminal domain homologous to saposin-like proteins (SAPLIPs). In addition to this, a carboxy(C)-terminal domain resembling the SAP-domain of Ku70 has been noted in the structure of analysis in Mesencephalic Astrocyte-Derived Neurotrophic Factor. Known to reduce or prevent the proapoptotic activity, or cell death, of BAX, carboxy(C)-terminal domain resembling the SAP-domain of Ku70 may enable MANF to protect cell death caused by ER stress.
Studies have shown that Mesencephalic Astrocyte-Derived Neurotrophic Factor interacts with GRP78. As GRP78 is associated with ER stress, the interaction between Mesencephalic Astrocyte-Derived Neurotrophic Factor and GRP78 gives a clear indication of how MANF can successfully regulate ER stress.
In addition to this, when there is a build-up of misfolded protein in the endoplasmic reticulum, HSPA5/BiP is released. Studies also suggest that Mesencephalic Astrocyte-Derived Neurotrophic Factor interacts with HSPA5/BiP, again linking the gene to the regulating of ER stress.
Furthermore, studies suggest that MANF could regulate AKT phosphorylation because it interacts with PIP4k2b in the endoplasmic reticulum. Observed during studies of the hypothalamus in mice, this has yet to be replicated in studies on human participants, so cannot necessarily be an accurate predictor of a MANF interaction within humans.
Whilst researchers are discovering more about how MANF works and what its role is, further analysis and testing is required in order to develop a deeper understanding of Mesencephalic Astrocyte-Derived Neurotrophic Factor and its potential in the treatment and prevention of disease.