51. Modelling the pathogenesis of X-linked distal hereditary motor neuropathy using patient-derived iPSCs
- Author
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Gonzalo Perez-Siles, Anthony Cutrupi, Melina Ellis, Jakob Kuriakose, Sharon La Fontaine, Di Mao, Motonari Uesugi, Reinaldo I. Takata, Carlos E. Speck-Martins, Garth Nicholson, Marina L. Kennerson, Annemieke Aartsma-Rus, James Dowling, and Maaike van Putten
- Subjects
0301 basic medicine ,Medicine (miscellaneous) ,lcsh:Medicine ,medicine.disease_cause ,Pathogenesis ,0302 clinical medicine ,Immunology and Microbiology (miscellaneous) ,Homeostasis ,Induced pluripotent stem cell ,Motor neurons ,Mutation ,Cell Differentiation ,Genetic Diseases, X-Linked ,3. Good health ,Mitochondria ,ATP7A Gene ,medicine.anatomical_structure ,Phenotype ,Spinal Cord ,lcsh:RB1-214 ,Research Article ,ATP7A ,Induced Pluripotent Stem Cells ,Karyotype ,Neuroscience (miscellaneous) ,Down-Regulation ,Biology ,Models, Biological ,General Biochemistry, Genetics and Molecular Biology ,dHMN ,Muscular Atrophy, Spinal ,03 medical and health sciences ,Downregulation and upregulation ,medicine ,lcsh:Pathology ,Humans ,Amino Acid Sequence ,Gene ,Base Sequence ,lcsh:R ,Fibroblasts ,030104 developmental biology ,nervous system ,Copper-Transporting ATPases ,Soma ,Energy Metabolism ,Neuroscience ,030217 neurology & neurosurgery ,Copper - Abstract
ATP7A encodes a copper-transporting P-type ATPase and is one of 23 genes in which mutations produce distal hereditary motor neuropathy (dHMN), a group of diseases characterized by length-dependent axonal degeneration of motor neurons. We have generated induced pluripotent stem cell (iPSC)-derived motor neurons from a patient with the p.T994I ATP7A gene mutation as an in vitro model for X-linked dHMN (dHMNX). Patient motor neurons show a marked reduction of ATP7A protein levels in the soma when compared to control motor neurons and failed to upregulate expression of ATP7A under copper-loading conditions. These results recapitulate previous findings obtained in dHMNX patient fibroblasts and in primary cells from a rodent model of dHMNX, indicating that patient iPSC-derived motor neurons will be an important resource for studying the role of copper in the pathogenic processes that lead to axonal degeneration in dHMNX., Summary: The authors describe a neuronal model to investigate how mutations in the copper transporter ATP7A cause axonal degeneration in the peripheral nervous system.
- Published
- 2019