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


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.

SUBMITTER: Chen H 

PROVIDER: S-EPMC4230530 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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

Chen Hong H   Qian Kun K   Du Zhongwei Z   Cao Jingyuan J   Petersen Andrew A   Liu Huisheng H   Blackbourn Lisle W LW   Huang CindyTzu-Ling CL   Errigo Anthony A   Yin Yingnan Y   Lu Jianfeng J   Ayala Melvin M   Zhang Su-Chun SC  

Cell stem cell 20140403 6


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 b  ...[more]

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