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Cell Stem Cell. 2014 Jun 5;14(6):796-809. doi: 10.1016/j.stem.2014.02.004. Epub 2014 Apr 3.

Modeling ALS with iPSCs reveals that mutant SOD1 misregulates neurofilament balance in motor neurons.

Author information

1
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.
2
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.
3
Waisman Center, University of Wisconsin, Madison, WI 53705, USA.
4
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.

Abstract

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.

PMID:
24704493
PMCID:
PMC4230530
DOI:
10.1016/j.stem.2014.02.004
[Indexed for MEDLINE]
Free PMC Article
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