Modelling the pathogenesis of X-linked distal hereditary motor neuropathy using patient-derived iPSCs
| Autor: | 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, Maaike van Putten |
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| Rok vydání: | 2019 |
| Předmět: |
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 |
| Zdroj: | Disease Models & Mechanisms Disease Models & Mechanisms, Vol 13, Iss 2 (2020) |
| ISSN: | 1754-8411 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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