title: Appoptosin is a novel pro-apoptotic protein and mediates cell death in neurodegeneration.
abstract: Apoptosis is an essential cellular process in multiple diseases and a major pathway for neuronal death in neurodegeneration. The detailed signaling events/pathways leading to apoptosis, especially in neurons, require further elucidation. Here we identify a β-amyloid precursor protein (APP)-interacting protein, designated as appoptosin, whose levels are upregulated in brain samples from Alzheimer's disease and infarct patients, and in rodent stroke models, as well as in neurons treated with β-amyloid (Aβ) and glutamate. We further demonstrate that appoptosin induces reactive oxygen species release and intrinsic caspase-dependent apoptosis. The physiological function of appoptosin is to transport/exchange glycine/5-amino-levulinic acid across the mitochondrial membrane for heme synthesis. Downregulation of appoptosin prevents cell death and caspase activation caused by glutamate or Aβ insults. APP modulates appoptosin-mediated apoptosis through interaction with appoptosin. Our study identifies appoptosin as a crucial player in apoptosis and a novel pro-apoptotic protein involved in neuronal cell death, providing a possible new therapeutic target for neurodegenerative disorders.
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research and Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian 361005, China.
authors.forename: Han
authors.initials: H
authors.lastname: Zhang
authors.forename: Yun-wu
authors.initials: YW
authors.lastname: Zhang
authors.forename: Yaomin
authors.initials: Y
authors.lastname: Chen
authors.forename: Xiumei
authors.initials: X
authors.lastname: Huang
authors.forename: Fangfang
authors.initials: F
authors.lastname: Zhou
authors.forename: Weiwei
authors.initials: W
authors.lastname: Wang
authors.forename: Bo
authors.initials: B
authors.lastname: Xian
authors.forename: Xian
authors.initials: X
authors.lastname: Zhang
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.forename: Quan
authors.initials: Q
authors.lastname: Chen
authors.forename: Jing-Dong J
authors.initials: JD
authors.lastname: Han
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
authors.forename: Francesca-Fang
authors.initials: FF
authors.lastname: Liao
authors.forename: Ye-Guang
authors.initials: YG
authors.lastname: Chen
authors.forename: Huaxi
authors.initials: H
authors.lastname: Xu
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000502:physiology*; D020520:Brain Infarction / Q000473:pathology; D020169:Caspases / Q000502:physiology; D016923:Cell Death / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D005260:Female; D005816:Genetic Complementation Test; D006418:Heme / Q000096:biosynthesis; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism; D009410:Nerve Degeneration / Q000235:genetics / Q000473:pathology*; D009474:Neurons / Q000473:pathology / Q000502:physiology; D011247:Pregnancy; D034622:RNA Interference; D051381:Rats; D017382:Reactive Oxygen Species
chemical_list: D016564:Amyloid beta-Protein Precursor; D017304:Annexin A5; D051017:Apoptosis Regulatory Proteins; D017382:Reactive Oxygen Species; D006418:Heme; D020169:Caspases