[Molecular mechanisms of differentiation and death of human neurons: with special reference to necdin and APP].
To elucidate the mechanisms underlying physiological development and neurodegenerative disorders of the human brain, information about molecular cell biology of human neurons is indispensable. Necdin, which is expressed in postmitotic neurons, binds to viral oncoproteins and the cell-cycle-related transcription factors E2F and p53. Ectopic expression of necdin in proliferative cells suppresses cell division. Necdin is expressed in neurons in phylogenetically old brain areas such as the brain stem and hypothalamus. The human necdin gene, which resides in the chromosome 15q11-q12 region, is not expressed in the Prader-Willi syndrome, suggesting that necdin is responsible for the pathogenesis of this genomic-imprinting-related neurobehavioral disorder. The Alzheimer amyloid precursor protein (APP) is a membrane-bound protein that is abundantly expressed in postmitotic neurons. The proteolytic processing of APP generates A beta, which is deposited in the brains of patients with Alzheimer's disease. APP is strongly expressed in neurons in phylogenetically new brain areas such as human association cortices. When APP is overexpressed in postomitotic neurons differentiated from human embryonal carcinoma by adenovirus-mediated gene transfer, it induces typical apoptosis through caspase-3 activation. Thus APP may be a proapoptotic molecule involved in neuronal death in Alzheimer's disease.
Yoshikawa
K
K
Division of Regulation of Macromolecular Functions, Institute for Protein Research, Osaka University, Yamadagaoka 3-2, Suita, 565-0871 Japan.
D000544:Alzheimer Disease / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000502:physiology; D017209:Apoptosis / Q000235:genetics*; D053148:Caspase 3; D020169:Caspases / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics*; D018392:Genomic Imprinting; D006801:Humans; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology; D009474:Neurons / Q000166:cytology* / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology; D011218:Prader-Willi Syndrome / Q000235:genetics
D016564:Amyloid beta-Protein Precursor; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C069766:necdin; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases