Modeling ALS with iPSCs reveals that mutant SOD1 misregulates neurofilament balance in motor neurons.
Amyotrophic lateral sclerosis (ALS) presents motoneuron (MN)-selective protein inclusions and axonal degeneration but the underlying mechanisms of such are unknown. Using induced pluripotent cells (iPSCs) from patients with mutation in the Cu/Zn superoxide dismutase (SOD1) gene, we show that spinal MNs, but rarely non-MNs, exhibited neurofilament (NF) aggregation followed by neurite degeneration when glia were not present. These changes were associated with decreased stability of NF-L mRNA and binding of its 3' UTR by mutant SOD1 and thus altered protein proportion of NF subunits. Such MN-selective changes were mimicked by expression of a single copy of the mutant SOD1 in human embryonic stem cells and were prevented by genetic correction of the SOD1 mutation in patient's iPSCs. Importantly, conditional expression of NF-L in the SOD1 iPSC-derived MNs corrected the NF subunit proportion, mitigating NF aggregation and neurite degeneration. Thus, NF misregulation underlies mutant SOD1-mediated NF aggregation and axonal degeneration in ALS MNs.
Department of Rehabilitation Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Waisman Center, University of Wisconsin, Madison, WI 53705, USA.
Hong
H
Chen
Reproductive Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Waisman Center, University of Wisconsin, Madison, WI 53705, USA.
Kun
K
Qian
Waisman Center, University of Wisconsin, Madison, WI 53705, USA.
Zhongwei
Z
Du
Waisman Center, University of Wisconsin, Madison, WI 53705, USA.
Jingyuan
J
Cao
Waisman Center, University of Wisconsin, Madison, WI 53705, USA.
Andrew
A
Petersen
Waisman Center, University of Wisconsin, Madison, WI 53705, USA.
Huisheng
H
Liu
Waisman Center, University of Wisconsin, Madison, WI 53705, USA.
Lisle W
LW
Blackbourn
Waisman Center, University of Wisconsin, Madison, WI 53705, USA.
CindyTzu-Ling
CL
Huang
Waisman Center, University of Wisconsin, Madison, WI 53705, USA.
Anthony
A
Errigo
Waisman Center, University of Wisconsin, Madison, WI 53705, USA.
Yingnan
Y
Yin
Waisman Center, University of Wisconsin, Madison, WI 53705, USA.
Jianfeng
J
Lu
Waisman Center, University of Wisconsin, Madison, WI 53705, USA.
Melvin
M
Ayala
Waisman Center, University of Wisconsin, Madison, WI 53705, USA; Department of Neuroscience and Department of Neurology, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705, USA. Electronic address: zhang@waisman.wisc.edu.
Su-Chun
SC
Zhang
D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism* / Q000473:pathology; D008954:Models, Biological; D009046:Motor Neurons / Q000378:metabolism*; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
D050505:Mutant Proteins; C000606290:SOD1 protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1