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read the link man...
the big thing to notice though, is of late, there is scientific acceptance of MANF being awesome. not so much phrasing of, there is eveidence for, or recent research suggests. more like, shit is magic, it has lots of emerging therapies in big indications, but we want to know why it works
Oxidizing environment is essential for protein folding and functions in the ER of
eukaryotic cells1–3. The Ero1-PDI enzymatic cascade in the ER mediates the oxygendependent
disulfide bond formation and proper folding of transmembrane or secreted
peer-reviewed) is the author/funder. It is made available under a CC-BY-NC-ND 4.0 International license.
bioRxiv preprint first posted online Feb. 11, 2018; doi: http://dx.doi.org/10.1101/263731. The copyright holder for this preprint (which was not
3
proteins. Severe hypoxia (reduced ambient oxygen), as frequently occurs in ischemic
and neoplastic disorders, causes cellular ER stress response independently of the wellcharacterized
Hypoxia Inducible Factor (HIF) pathway4–6. Eukaryotic cells actively
maintain protein folding and redox homeostasis in the ER upon hypoxic and oxidative
stresses by regulating numerous cellular factors to promote normal physiological
functions and cytoprotection. Among such factors that have been studied, MANF is an
enigmatic family of proteins with rather unique mode and mechanisms of action.
Mammalian MANF was initially identified for its neurotrophic effects on
dopaminergic neurons7
. It is a 20 kD small secreted protein that exhibits no amino acid
sequence similarities to any other classical families of target-derived neurotrophic
factors, including GDNF, NT3 and BDNF. MANF family proteins are highly evolutionarily
conserved with both human and Drosophila orthologues being capable of promoting
dopamine neuron survival8–10. Its N-terminus contains a structural fold similar to Saposin
proteins while its C-terminus contains a SAP (SAF-A/B, Acinus, and PIAS) domain
similar to that of Ku70, an inhibitor of proapoptotic Bax11,12. MANF is widely expressed
in the body, with levels particularly high in the nervous system, kidney, heart and
pancreatic β cells13–15. Cellular MANF abundance and secretion are strongly upregulated
by ER stress-related stimuli, including hypoxia, ischemia, chemical treatments
with tunicamycin or tharpsigargin13,15–17. Because of its secretion from cardiomyocyte
and autocrine/paracrine effects on cardiovascular functions, MANF has been termed
“cardiomyokine” playing critical roles in cardioprotection, hypertrophy and heart failure18.
MANF KO mice are diabetic with abnormal activation of unfolded protein response in
pancreatic islets, while its gain-of-function by exogenous MANF addition, physiological
peer-reviewed) is the author/funder. It is made available under a CC-BY-NC-ND 4.0 International license.
bioRxiv preprint first posted online Feb. 11, 2018; doi: http://dx.doi.org/10.1101/263731. The copyright holder for this preprint (which was not
4
up-regulation or transgenic MANF overexpression has been shown to protect
dopaminergic neurons, cerebral neurons, Purkinje cells, retinal neurons, pancreatic β
cells and cardiomyocytes from degeneration or cell death7,8,13,19–22.
Despite potent cytoprotective effects and emerging therapeutic potentials of
MANF for neurodegenerative, cardiovascular, diabetic and ischemic disorders, how
extracellular MANF signals to cells and confers cytoprotection has remained largely
elusive. No MANF receptor has been identified despite over a decade of research since
its cytoprotective activity was discovered in 2003. Although it has been suggested that
MANF might bind to certain cell surface lipids via its N-terminal Saposin-like domain, the
molecular identity of MANF-binding lipids and how its potential lipid-binding ability might
contribute to cytoprotection are unknown. Understanding the mechanisms of action of
extracellular MANF in cytoprotection thus remains a key challenge of the field.
the big thing to notice though, is of late, there is scientific acceptance of MANF being awesome. not so much phrasing of, there is eveidence for, or recent research suggests. more like, shit is magic, it has lots of emerging therapies in big indications, but we want to know why it works
Oxidizing environment is essential for protein folding and functions in the ER of
eukaryotic cells1–3. The Ero1-PDI enzymatic cascade in the ER mediates the oxygendependent
disulfide bond formation and proper folding of transmembrane or secreted
peer-reviewed) is the author/funder. It is made available under a CC-BY-NC-ND 4.0 International license.
bioRxiv preprint first posted online Feb. 11, 2018; doi: http://dx.doi.org/10.1101/263731. The copyright holder for this preprint (which was not
3
proteins. Severe hypoxia (reduced ambient oxygen), as frequently occurs in ischemic
and neoplastic disorders, causes cellular ER stress response independently of the wellcharacterized
Hypoxia Inducible Factor (HIF) pathway4–6. Eukaryotic cells actively
maintain protein folding and redox homeostasis in the ER upon hypoxic and oxidative
stresses by regulating numerous cellular factors to promote normal physiological
functions and cytoprotection. Among such factors that have been studied, MANF is an
enigmatic family of proteins with rather unique mode and mechanisms of action.
Mammalian MANF was initially identified for its neurotrophic effects on
dopaminergic neurons7
. It is a 20 kD small secreted protein that exhibits no amino acid
sequence similarities to any other classical families of target-derived neurotrophic
factors, including GDNF, NT3 and BDNF. MANF family proteins are highly evolutionarily
conserved with both human and Drosophila orthologues being capable of promoting
dopamine neuron survival8–10. Its N-terminus contains a structural fold similar to Saposin
proteins while its C-terminus contains a SAP (SAF-A/B, Acinus, and PIAS) domain
similar to that of Ku70, an inhibitor of proapoptotic Bax11,12. MANF is widely expressed
in the body, with levels particularly high in the nervous system, kidney, heart and
pancreatic β cells13–15. Cellular MANF abundance and secretion are strongly upregulated
by ER stress-related stimuli, including hypoxia, ischemia, chemical treatments
with tunicamycin or tharpsigargin13,15–17. Because of its secretion from cardiomyocyte
and autocrine/paracrine effects on cardiovascular functions, MANF has been termed
“cardiomyokine” playing critical roles in cardioprotection, hypertrophy and heart failure18.
MANF KO mice are diabetic with abnormal activation of unfolded protein response in
pancreatic islets, while its gain-of-function by exogenous MANF addition, physiological
peer-reviewed) is the author/funder. It is made available under a CC-BY-NC-ND 4.0 International license.
bioRxiv preprint first posted online Feb. 11, 2018; doi: http://dx.doi.org/10.1101/263731. The copyright holder for this preprint (which was not
4
up-regulation or transgenic MANF overexpression has been shown to protect
dopaminergic neurons, cerebral neurons, Purkinje cells, retinal neurons, pancreatic β
cells and cardiomyocytes from degeneration or cell death7,8,13,19–22.
Despite potent cytoprotective effects and emerging therapeutic potentials of
MANF for neurodegenerative, cardiovascular, diabetic and ischemic disorders, how
extracellular MANF signals to cells and confers cytoprotection has remained largely
elusive. No MANF receptor has been identified despite over a decade of research since
its cytoprotective activity was discovered in 2003. Although it has been suggested that
MANF might bind to certain cell surface lipids via its N-terminal Saposin-like domain, the
molecular identity of MANF-binding lipids and how its potential lipid-binding ability might
contribute to cytoprotection are unknown. Understanding the mechanisms of action of
extracellular MANF in cytoprotection thus remains a key challenge of the field.
9
