Mesencephalic astrocyte-derived neurotrophic factor (MANF) has a unique mechanism to rescue apoptotic neurons.
Mesencephalic astrocyte-derived neurotrophic factor (MANF) protects neurons and repairs the Parkinson disease-like symptoms in a rat 6-hydroxydopamine model. We show a three-dimensional solution structure of human MANF that differs drastically from other neurotrophic factors. Remarkably, the C-terminal domain of MANF (C-MANF) is homologous to the SAP domain of Ku70, a well known inhibitor of proapoptotic Bax (Bcl-2-associated X protein). Cellular studies confirm that MANF and C-MANF protect neurons intracellularly as efficiently as Ku70.
Program in Structural Biology and Biophysics, Institute of Biotechnology, University of Helsinki, FI-00014 Helsinki, Finland.
Maarit
M
Hellman
Urmas
U
Arumäe
Li-ying
LY
Yu
Päivi
P
Lindholm
Johan
J
Peränen
Mart
M
Saarma
Perttu
P
Permi
D000818:Animals; D034961:Antigens, Nuclear / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D000072200:Ku Autoantigen; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D019906:Nuclear Magnetic Resonance, Biomolecular; D016627:Oxidopamine / Q000009:adverse effects / Q000494:pharmacology; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D040681:Structural Homology, Protein; D013565:Sympatholytics / Q000009:adverse effects / Q000493:pharmacokinetics; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
D034961:Antigens, Nuclear; C494826:BAX protein, human; C494828:Bax protein, rat; D004268:DNA-Binding Proteins; C099695:MANF protein, human; C546826:MANF protein, rat; D009414:Nerve Growth Factors; D011506:Proteins; D013565:Sympatholytics; D051028:bcl-2-Associated X Protein; D016627:Oxidopamine; C000606509:Xrcc6 protein, human; C000606511:Xrcc6 protein, rat; D000072200:Ku Autoantigen