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Insights into the pathogenesis of ATP1A1 ‐related CMT disease using patient‐specific iPSCs
Author(s) -
Manganelli Fiore,
Parisi Silvia,
Nolano Maria,
Miceli Francesco,
Tozza Stefano,
Pisciotta Chiara,
Iodice Rosa,
Provitera Vincenzo,
Cicatiello Rita,
Zuchner Stephan,
Taglialatela Maurizio,
Russo Tommaso,
Santoro Lucio
Publication year - 2019
Publication title -
journal of the peripheral nervous system
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1
H-Index - 67
eISSN - 1529-8027
pISSN - 1085-9489
DOI - 10.1111/jns.12357
Subject(s) - induced pluripotent stem cell , pathogenesis , microbiology and biotechnology , cellular differentiation , mitosis , phenotype , biology , in vitro , medicine , neuroscience , gene , genetics , embryonic stem cell , immunology
The development of patient‐specific induced pluripotent stem cells (iPSCs) offered interesting insights in modeling the pathogenesis of Charcot‐Marie‐Tooth (CMT) disease and thus we decided to explore the phenotypes of iPSCs derived from a single CMT patient carrying a mutant ATP1A1 allele (p.Pro600Ala). iPSCs clones generated from CMT and control fibroblasts, were induced to differentiate into neural precursors and then into post‐mitotic neurons. Control iPSCs differentiated into neuronal precursors and then into post‐mitotic neurons within 6‐8 days. On the contrary, the differentiation of CMT iPSCs was clearly defective. Electrophysiological properties confirmed that post‐mitotic neurons were less mature compared to the normal counterpart. The impairment of in vitro differentiation of CMT iPSCs only concerned with the neuronal pathway, because they were able to differentiate into mesendodermal cells and other ectodermal derivatives. ATP1A1 was undetectable in the few neuronal cells derived from CMT iPSCs. ATP1A1 gene mutation (p.Pro600Ala), responsible for a form of axonal CMT disease, is associated in vitro with a dramatic alteration of the differentiation of patient‐derived iPSCs into post‐mitotic neurons. Thus, the defect in neuronal cell development might lead in vivo to a decreased number of mature neurons in ATP1A1‐CMT disease.