Differentiation and molecular pathological analysis of motor neurons in a case of spinal muscular atrophy
Objective To explore the molecular pathologic phenotype of spinal and bulbar muscular atrophy(SBMA)using motor neurons derived from induced pluripotent stem cells(iPSCs)from SBMA patients.Methods Skin fibro-blasts from one SBMA patient and one healthy control were extracted and reprogrammed into iPSCs;iPSCs were in-duced into motor neurons progenitor(MNP)and differentiated into mature motor neurons(mMN);immunofluores-cence staining was used to study cell proliferation and apoptosis,and the formation of intranuclear inclusion bodies was detected.Results The patient was a 35-year-old male who presented with proximal weakness of the extremities,hand tremors,and hypogonadism.Skeletal muscle biopsy showed pathologic changes of neurogenic damage.Peripheral blood capillary electrophoresis showed 44 repeats of CAG in exon 1 of the AR gene.iPSCs all expressed stemness markers,had normal karyotypes,and were able to differentiate randomly into trichodermal cell types.No intranuclear inclusion bodies were seen in patient iPSCs and MNP,but intranuclear inclusion bodies were more typical in mMN.Compared with normal controls,the patients'MNP had an increased proportion of apoptosis and a decreased proportion of prolifer-ation.Conclusion The iPSCs of SBMA patients carried pathogenic mutations,and their differentiated mMNs contained typical intranuclear inclusion bodies,which accurately mimicked the molecular pathological features of the disease and provided an ideal model for the subsequent mechanism study and drug target discovery.
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