title: Autophagy has a key role in the pathophysiology of schizophrenia.
abstract: Autophagy is a process preserving the balance between synthesis, degradation and recycling of cellular components and is therefore essential for neuronal survival and function. Several key proteins govern the autophagy pathway including beclin1 and microtubule associated protein 1 light chain 3 (LC3). Here, we show a brain-specific reduction in beclin1 expression in postmortem hippocampus of schizophrenia patients, not detected in peripheral lymphocytes. This is in contrast with activity-dependent neuroprotective protein (ADNP) and ADNP2, which we have previously found to be deregulated in postmortem hippocampal samples from schizophrenia patients, but that now showed a significantly increased expression in lymphocytes from related patients, similar to increases in the anti-apoptotic, beclin1-interacting, Bcl2. The increase in ADNP was associated with the initial stages of the disease, possibly reflecting a compensatory effect. The increase in ADNP2 might be a consequence of neuroleptic treatment, as seen in rats subjected to clozapine treatment. ADNP haploinsufficiency in mice, which results in age-related neuronal death, cognitive and social dysfunction, exhibited reduced hippocampal beclin1 and increased Bcl2 expression (mimicking schizophrenia and normal human aging). At the protein level, ADNP co-immunoprecipitated with LC3B suggesting a direct association with the autophagy process and paving the path to novel targets for drug design.
authors.affiliation: Adams Super Center for Brain Studies, and Sagol School of Neuroscience, Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Merenlender-Wagner
authors.affiliation: Adams Super Center for Brain Studies, and Sagol School of Neuroscience, Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Malishkevich
authors.affiliation: Adams Super Center for Brain Studies, and Sagol School of Neuroscience, Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Z
authors.initials: Z
authors.lastname: Shemer
authors.affiliation: 1] Molecular Psychiatry Laboratory, Florey Institute for Neuroscience and Mental Health, University of Melbourne, Victoria, Australia [2] Department of Psychiatry, University of Melbourne, Victoria, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Udawela
authors.affiliation: 1] Molecular Psychiatry Laboratory, Florey Institute for Neuroscience and Mental Health, University of Melbourne, Victoria, Australia [2] Department of Psychiatry, University of Melbourne, Victoria, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Gibbons
authors.affiliation: 1] Molecular Psychiatry Laboratory, Florey Institute for Neuroscience and Mental Health, University of Melbourne, Victoria, Australia [2] Department of Psychiatry, University of Melbourne, Victoria, Australia.
authors.forename: E
authors.initials: E
authors.lastname: Scarr
authors.affiliation: 1] Molecular Psychiatry Laboratory, Florey Institute for Neuroscience and Mental Health, University of Melbourne, Victoria, Australia [2] Department of Psychiatry, University of Melbourne, Victoria, Australia.
authors.forename: B
authors.initials: B
authors.lastname: Dean
authors.affiliation: 1] Psychiatry Research Unit, Beer-Sheva, Israel [2] Mental Health Center, Beer-Sheva, Israel.
authors.forename: J
authors.initials: J
authors.lastname: Levine
authors.affiliation: 1] Psychiatry Research Unit, Beer-Sheva, Israel [2] Mental Health Center, Beer-Sheva, Israel [3] Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: G
authors.initials: G
authors.lastname: Agam
authors.affiliation: Adams Super Center for Brain Studies, and Sagol School of Neuroscience, Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: I
authors.initials: I
authors.lastname: Gozes
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000941:ethics* / Q000235:genetics / Q000502:physiology; D000071186:Beclin-1; D016022:Case-Control Studies; D002461:Cell Line, Transformed; D003024:Clozapine / Q000494:pharmacology; D005260:Female; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology*; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics; D009447:Neuroblastoma / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012559:Schizophrenia / Q000473:pathology* / Q000503:physiopathology*; D055815:Young Adult; D051025:bcl-Associated Death Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C492178:ADNP protein, human; D014150:Antipsychotic Agents; D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C512829:Becn1 protein, rat; D018398:Homeodomain Proteins; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D051025:bcl-Associated Death Protein; D003024:Clozapine