TY - JOUR
T1 - Enhanced axonal regeneration of ALS patient iPSC-derived motor neurons harboring SOD1A4V mutation
AU - Marshall, Katherine L.
AU - Rajbhandari, Labchan
AU - Venkatesan, Arun
AU - Maragakis, Nicholas J.
AU - Farah, Mohamed H.
N1 - Funding Information:
The authors thank Aundree Hermawan, John Maragakis, Arens Taga, Maria Majid, and Erin Beebe for their technical assistance. Figure 1 A was created with Biorender.com. We thank Michele Pucak and the Neuroscience Multiphoton Imaging Core for their imaging assistance. We also thank Dr. Leah Jager and the Johns Hopkins ICTR biostatistics consulting service for their helpful discussions on data analysis.
Funding Information:
Maryland Stem Cell Research Fund: 2019-MSCRFD-5093 (M.H.F.), 2022-MSCRFF-5833 (K.L.M.); NIH: R21NS130900 (M.H.F.), R01NS117608 (N.J.M.).
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, characterized by degeneration of upper and lower motor neurons that leads to muscle weakness, paralysis, and death, but the effects of disease-causing mutations on axonal outgrowth of neurons derived from human induced pluripotent stem cells (iPSC)-derived motor neurons (hiPSC-MN) are poorly understood. The use of hiPSC-MN is a promising tool to develop more relevant models for target identification and drug development in ALS research, but questions remain concerning the effects of distinct disease-causing mutations on axon regeneration. Mutations in superoxide dismutase 1 (SOD1) were the first to be discovered in ALS patients. Here, we investigated the effect of the SOD1A4V mutation on axonal regeneration of hiPSC-MNs, utilizing compartmentalized microfluidic devices, which are powerful tools for studying hiPSC-MN distal axons. Surprisingly, SOD1+/A4V hiPSC-MNs regenerated axons more quickly following axotomy than those expressing the native form of SOD1. Though initial axon regrowth was not significantly different following axotomy, enhanced regeneration was apparent at later time points, indicating an increased rate of outgrowth. This regeneration model could be used to identify factors that enhance the rate of human axon regeneration.
AB - Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, characterized by degeneration of upper and lower motor neurons that leads to muscle weakness, paralysis, and death, but the effects of disease-causing mutations on axonal outgrowth of neurons derived from human induced pluripotent stem cells (iPSC)-derived motor neurons (hiPSC-MN) are poorly understood. The use of hiPSC-MN is a promising tool to develop more relevant models for target identification and drug development in ALS research, but questions remain concerning the effects of distinct disease-causing mutations on axon regeneration. Mutations in superoxide dismutase 1 (SOD1) were the first to be discovered in ALS patients. Here, we investigated the effect of the SOD1A4V mutation on axonal regeneration of hiPSC-MNs, utilizing compartmentalized microfluidic devices, which are powerful tools for studying hiPSC-MN distal axons. Surprisingly, SOD1+/A4V hiPSC-MNs regenerated axons more quickly following axotomy than those expressing the native form of SOD1. Though initial axon regrowth was not significantly different following axotomy, enhanced regeneration was apparent at later time points, indicating an increased rate of outgrowth. This regeneration model could be used to identify factors that enhance the rate of human axon regeneration.
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U2 - 10.1038/s41598-023-31720-7
DO - 10.1038/s41598-023-31720-7
M3 - Article
C2 - 37020097
AN - SCOPUS:85151794526
SN - 2045-2322
VL - 13
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 5597
ER -