ABSTRACT
Methodologies for generating functional neuronal cells directly from human fibroblasts [induced neuronal (iN) cells] have been recently developed, but the research so far has only focused on technical refinements or recapitulation of known pathological phenotypes. A critical question is whether this novel technology will contribute to elucidation of novel disease mechanisms or evaluation of therapeutic strategies. Here we have addressed this question by studying Tay-Sachs disease, a representative lysosomal storage disease, and Dravet syndrome, a form of severe myoclonic epilepsy in infancy, using human iN cells with feature of immature postmitotic glutamatergic neuronal cells. In Tay-Sachs disease, we have successfully characterized canonical neuronal pathology, massive accumulation of GM2 ganglioside, and demonstrated the suitability of this novel cell culture for future drug screening. In Dravet syndrome, we have identified a novel functional phenotype that was not suggested by studies of classical mouse models and human autopsied brains. Taken together, the present study demonstrates that human iN cells are useful for translational neuroscience research to explore novel disease mechanisms and evaluate therapeutic compounds. In the future, research using human iN cells with well-characterized genomic landscape can be integrated into multidisciplinary patient-oriented research on neuropsychiatric disorders to address novel disease mechanisms and evaluate therapeutic strategies.
Subject(s)
Epilepsies, Myoclonic/metabolism , Fibroblasts/metabolism , G(M2) Ganglioside/metabolism , Neurons/metabolism , Tay-Sachs Disease/metabolism , 1-Deoxynojirimycin/analogs & derivatives , 1-Deoxynojirimycin/pharmacology , Action Potentials/drug effects , Basic Helix-Loop-Helix Transcription Factors/genetics , Basic Helix-Loop-Helix Transcription Factors/metabolism , Cell Differentiation , Epilepsies, Myoclonic/pathology , Fibroblasts/drug effects , Fibroblasts/pathology , Gene Expression , Genetic Vectors/chemistry , Genetic Vectors/metabolism , Glycoside Hydrolase Inhibitors/pharmacology , Humans , Lentivirus/genetics , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Neurons/drug effects , Neurons/pathology , Plasmids/chemistry , Plasmids/metabolism , Primary Cell Culture , Tay-Sachs Disease/pathology , Transcription Factors/genetics , Transcription Factors/metabolism , Transduction, Genetic , TransgenesABSTRACT
To determine which analysis is suitable to examine the dentofacial skeletal pattern characteristics of the obstructive sleep apnea syndrome (OSAS), we took lateral cephalograms of 44 Japanese OSAS patients and 34 Japanese non-OSAS controls. By Ricketts analysis, we found significant differences between OSAS patients and non-OSAS controls on facial axis, lower facial height and total facial height, which showed that Japanese OSAS patients have dolico facial patterns. However, by Downs-Northwestern analysis, we did not find any significant difference between OSAS patients and non-OSAS controls using the same cephalograms as the Ricketts analysis.
Subject(s)
Cephalometry/methods , Sleep Apnea, Obstructive/diagnosis , Adult , Face/anatomy & histology , Female , Humans , Male , Mandible/anatomy & histology , Middle Aged , Reference Values , Severity of Illness IndexABSTRACT
To analyze the facial patterns of obstructive sleep apnea syndrome (OSAS) patients, we took lateral cephalograms of 31 OSAS patients and 26 non-OSAS controls and utilized Ricketts' method. In addition, we measured the hyoid bone position, the length of mandibular plane to H-point, the length of soft palate, and lower pharynx. The facial patterns of OSAS patients were dolico, the hyoid bone was positioned low, the soft palate was longer and the width of the airway was narrower than that of the non-OSAS controls.
