Journal article
Axonal Charcot–Marie–Tooth disease patient-derived motor neurons demonstrate disease-specific phenotypes including abnormal electrophysiological properties
Experimental neurology, Vol.263, pp.190-199
01/2015
DOI: 10.1016/j.expneurol.2014.10.005
PMCID: PMC4262589
PMID: 25448007
Abstract
Charcot–Marie–Tooth (CMT) disease is a group of inherited peripheral neuropathies associated with mutations or copy number variations in over 70 genes encoding proteins with fundamental roles in the development and function of Schwann cells and peripheral axons. Here, we used iPSC-derived cells to identify common pathophysiological mechanisms in axonal CMT.
iPSC lines from patients with two distinct forms of axonal CMT (CMT2A and CMT2E) were differentiated into spinal cord motor neurons and used to study axonal structure and function and electrophysiological properties in vitro.
iPSC-derived motor neurons exhibited gene and protein expression, ultrastructural and electrophysiological features of mature primary spinal cord motor neurons. Cytoskeletal abnormalities were found in neurons from a CMT2E (NEFL) patient and corroborated by a mouse model of the same NEFL point mutation. Abnormalities in mitochondrial trafficking were found in neurons derived from this patient, but were only mildly present in neurons from a CMT2A (MFN2) patient. Novel electrophysiological abnormalities, including reduced action potential threshold and abnormal channel current properties were observed in motor neurons derived from both of these patients.
Human iPSC-derived motor neurons from axonal CMT patients replicated key pathophysiological features observed in other models of MFN2 and NEFL mutations, including abnormal cytoskeletal and mitochondrial dynamics. Electrophysiological abnormalities found in axonal CMT iPSC-derived human motor neurons suggest that these cells are hyperexcitable and have altered sodium and calcium channel kinetics. These findings may provide a new therapeutic target for this group of heterogeneous inherited neuropathies.
•Patient-derived spinal motor neurons closely resemble primary neurons.•CMT2E neurons have disrupted neurofilament and axonal mitochondrial dynamics.•CMT2A and CMT2E neurons are hyperexcitable and have altered ion channel kinetics.•Therefore, our results suggest a novel potential target for drug therapy in CMT.•Our data supports the use of cellular reprogramming to study Inherited Neuropathies.
Details
- Title: Subtitle
- Axonal Charcot–Marie–Tooth disease patient-derived motor neurons demonstrate disease-specific phenotypes including abnormal electrophysiological properties
- Creators
- Mario A Saporta - Department of Neurology, University of Iowa, USAVu Dang - iPierian Inc., USADmitri Volfson - iPierian Inc., USABende Zou - AfaSci Inc., USAXinmin (Simon) Xie - AfaSci Inc., USAAdijat Adebola - Department of Pathology and Cell Biology, Columbia University Medical Center, USARonald K Liem - Department of Pathology and Cell Biology, Columbia University Medical Center, USAMichael Shy - Department of Neurology, University of Iowa, USAJohn T Dimos - iPierian Inc., USA
- Resource Type
- Journal article
- Publication Details
- Experimental neurology, Vol.263, pp.190-199
- DOI
- 10.1016/j.expneurol.2014.10.005
- PMID
- 25448007
- PMCID
- PMC4262589
- NLM abbreviation
- Exp Neurol
- ISSN
- 0014-4886
- eISSN
- 1090-2430
- Publisher
- Elsevier Inc
- Grant note
- DOI: 10.13039/100000065, name: NINDS, award: 5U54NS065712; DOI: 10.13039/100000002, name: NIH, award: R01MH078194, R43NS065555, R43 NS073311, RC1 NS068131
- Language
- English
- Date published
- 01/2015
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Iowa Neuroscience Institute
- Record Identifier
- 9984020636102771
Metrics
23 Record Views