Expression of DISC1 binding partners is reduced in schizophrenia and associated with DISC1 SNPs.
DISC1 has been identified as a schizophrenia susceptibility gene based on linkage and SNP association studies and clinical data suggesting that risk SNPs impact on hippocampal structure and function. In cell and animal models, C-terminus-truncated DISC1 disrupts intracellular transport, neural architecture and migration, perhaps because it fails to interact with binding partners involved in neuronal differentiation such as fasciculation and elongation protein zeta-1 (FEZ1), platelet-activating factor acetylhydrolase, isoform Ib, PAFAH1B1 or lissencephaly 1 protein (LIS1) and nuclear distribution element-like (NUDEL). We hypothesized that altered expression of DISC1 and/or its molecular partners may underlie its pathogenic role in schizophrenia and explain its genetic association. We examined the expression of DISC1 and these selected binding partners as well as reelin, a protein in a related signaling pathway, in the hippocampus and dorsolateral prefrontal cortex of postmortem human brain patients with schizophrenia and controls. We found no difference in the expression of DISC1 or reelin mRNA in schizophrenia and no association with previously identified risk DISC1 SNPs. However, the expression of NUDEL, FEZ1 and LIS1 was each significantly reduced in the brain tissue from patients with schizophrenia and expression of each showed association with high-risk DISC1 polymorphisms. Although, many other DISC1 binding partners still need to be investigated, these data implicate genetically linked abnormalities in the DISC1 molecular pathway in the pathophysiology of schizophrenia.
Lipska
Barbara K
BK
Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA. lipskab@intra.nimh.nih.gov
Peters
Tricia
T
Hyde
Thomas M
TM
Halim
Nader
N
Horowitz
Cara
C
Mitkus
Shruti
S
Weickert
Cynthia Shannon
CS
Matsumoto
Mitsuyuki
M
Sawa
Akira
A
Straub
Richard E
RE
Vakkalanka
Radhakrishna
R
Herman
Mary M
MM
Weinberger
Daniel R
DR
Kleinman
Joel E
JE
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D014150:Antipsychotic Agents / Q000378:metabolism / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007223:Infant; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D000091042:Reelin Protein; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D020798:Two-Hybrid System Techniques
D048868:Adaptor Proteins, Signal Transducing; D014150:Antipsychotic Agents; D002352:Carrier Proteins; D015816:Cell Adhesion Molecules, Neuronal; C412476:DISC1 protein, human; D004268:DNA-Binding Proteins; D016326:Extracellular Matrix Proteins; C528597:FEZ1 protein, human; C118711:LZTS1 protein, human; D008869:Microtubule-Associated Proteins; C421108:NDEL1 protein, human; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D000091042:Reelin Protein; C000717129:Reln protein, rat; D025521:Tumor Suppressor Proteins; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C084102:PAFAH1B1 protein, human; C000717127:RELN protein, human; D012697:Serine Endopeptidases