TY - JOUR
T1 - Macrophage migration inhibitory factor as a chaperone inhibiting accumulation of misfolded SOD1
AU - Israelson, Adrian
AU - Ditsworth, Dara
AU - Sun, Shuying
AU - Song, Sung Won
AU - Liang, Jason
AU - Hruska-Plochan, Marian
AU - McAlonis-Downes, Melissa
AU - Abu-Hamad, Salah
AU - Zoltsman, Guy
AU - Shani, Tom
AU - Maldonado, Marcus
AU - Bui, Anh
AU - Navarro, Michael
AU - Zhou, Huilin
AU - Marsala, Martin
AU - Kaspar, Brian K.
AU - DaCruz, Sandrine
AU - Cleveland, Don W.
N1 - Funding Information:
We would like to thank Jean-Pierre Julien for the pEGFP-SOD1 vectors, Jurgen Bernhagen for providing the MIF vectors, and Neil Cashman for the DSE2 antibodies. We thank Kota Kamizato, Alex Kopelevich, Jon Artates, and Amanda Seelman for their technical assistance and Jennifer Santini for technical support at the UCSD Microscopy Core Facility, supported by UCSD Neuroscience Microscopy Shared Facility Grant P30 NS047101. This work has been supported by grants from the NIH (R01 NS27036 to D.W.C. and R01 NS644912 to B.K.K.). A.I. has been supported by a career development grant from the Muscular Dystrophy Association and a Marie Curie Career Integration Grant. D.D. is supported by an NIH postdoctoral fellowship. D.W.C. receives salary support from the Ludwig Institute for Cancer Research.
Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/4/8
Y1 - 2015/4/8
N2 - Mutations in superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by loss of motor neurons and accompanied by accumulation of misfolded SOD1 onto the cytoplasmic faces of intracellular organelles, including mitochondria and the endoplasmic reticulum (ER). Using inhibition of misfolded SOD1 deposition onto mitochondria as an assay, a chaperone activity abundant in nonneuronal tissues is now purified and identified to be the multifunctional macrophage migration inhibitory factor (MIF), whose activities include an ATP-independent protein folding chaperone. Purified MIF is shown to directly inhibit mutant SOD1 misfolding. Elevating MIF in neuronal cells suppresses accumulation of misfolded SOD1 and its association with mitochondria and the ER and extends survival of mutant SOD1-expressing motor neurons. Accumulated MIF protein is identified to be low in motor neurons, implicating correspondingly low chaperone activity as a component of vulnerability to mutant SOD1 misfolding and supporting therapies to enhance intracellular MIF chaperone activity.
AB - Mutations in superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by loss of motor neurons and accompanied by accumulation of misfolded SOD1 onto the cytoplasmic faces of intracellular organelles, including mitochondria and the endoplasmic reticulum (ER). Using inhibition of misfolded SOD1 deposition onto mitochondria as an assay, a chaperone activity abundant in nonneuronal tissues is now purified and identified to be the multifunctional macrophage migration inhibitory factor (MIF), whose activities include an ATP-independent protein folding chaperone. Purified MIF is shown to directly inhibit mutant SOD1 misfolding. Elevating MIF in neuronal cells suppresses accumulation of misfolded SOD1 and its association with mitochondria and the ER and extends survival of mutant SOD1-expressing motor neurons. Accumulated MIF protein is identified to be low in motor neurons, implicating correspondingly low chaperone activity as a component of vulnerability to mutant SOD1 misfolding and supporting therapies to enhance intracellular MIF chaperone activity.
UR - http://www.scopus.com/inward/record.url?scp=84930332449&partnerID=8YFLogxK
U2 - 10.1016/j.neuron.2015.02.034
DO - 10.1016/j.neuron.2015.02.034
M3 - Article
C2 - 25801706
AN - SCOPUS:84930332449
SN - 0896-6273
VL - 86
SP - 218
EP - 232
JO - Neuron
JF - Neuron
IS - 1
ER -