Refine
Year of publication
Document Type
- Article (22)
Has Fulltext
- yes (22)
Is part of the Bibliography
- no (22)
Keywords
- aging (2)
- lymphocytes (2)
- oxidative stress (2)
- presenilin-1 (2)
- 2-deoxy-D-ribose (1)
- AD patients (1)
- Activation markers (1)
- Aging (1)
- Alzheimer's disease (1)
- Alzheimer’s disease (1)
- Apoptosis (1)
- Bcl-2 (1)
- Bipolar disorder (1)
- CD69 expression (1)
- Cytokine expression (1)
- Depression (1)
- General practice (1)
- Genetics (1)
- Glutathione reductase (1)
- Immunosenescence (1)
- Lipid peroxidation (1)
- Lymphocytes (1)
- Medication changes (1)
- Multimorbidity (1)
- Multiple chronic conditions (1)
- Neurodegeneration (1)
- Neuroscience (1)
- Older adults (1)
- Oxidative stress (1)
- Polypharmacy (1)
- Presenilin (1)
- Proliferation (1)
- Reactive oxygen species (1)
- Superoxide dismutase (1)
- T lymphocyte subsets (1)
- Tyrosine phosphorylation (1)
- alzheimer’s disease (1)
- amyloid precursor protein (APP) (1)
- apoptosis (1)
- calcium (1)
- cell death (1)
- cytochrome c. (1)
- lymphocyte (1)
- mitochondrial dysfunction (1)
- piracetam (1)
- programmed cell death (1)
- reactive oxygen species (1)
- transgenic mice (1)
Institute
- Pharmazie (15)
- Medizin (7)
- Biowissenschaften (1)
- Physik (1)
- Präsidium (1)
Major mood disorders, which primarily include bipolar disorder and major depressive disorder, are the leading cause of disability worldwide and pose a major challenge in identifying robust risk genes. Here, we present data from independent large-scale clinical data sets (including 29 557 cases and 32 056 controls) revealing brain expressed protocadherin 17 (PCDH17) as a susceptibility gene for major mood disorders. Single-nucleotide polymorphisms (SNPs) spanning the PCDH17 region are significantly associated with major mood disorders; subjects carrying the risk allele showed impaired cognitive abilities, increased vulnerable personality features, decreased amygdala volume and altered amygdala function as compared with non-carriers. The risk allele predicted higher transcriptional levels of PCDH17 mRNA in postmortem brain samples, which is consistent with increased gene expression in patients with bipolar disorder compared with healthy subjects. Further, overexpression of PCDH17 in primary cortical neurons revealed significantly decreased spine density and abnormal dendritic morphology compared with control groups, which again is consistent with the clinical observations of reduced numbers of dendritic spines in the brains of patients with major mood disorders. Given that synaptic spines are dynamic structures which regulate neuronal plasticity and have crucial roles in myriad brain functions, this study reveals a potential underlying biological mechanism of a novel risk gene for major mood disorders involved in synaptic function and related intermediate phenotypes.
Poster presentation: Here we investigated the role of the amyloid precursor protein (APP) in regulation of Ca2+ store depletion-induced neural cell death. Ca2+ store depletion from the endoplasmic reticulum (ER) was induced by the SERCA (Sarco/Endoplasmic Reticulum Calcium ATPase) inhibitor thapsigargin which led to a rapid induction of the unfolded protein response (UPR) and a delayed activation of executioner caspases in the cultures. Overexpression of APP potently enhanced cytosolic Ca2+ levels and cell death after ER Ca2+ store depletion in comparison to vector-transfected controls. GeneChipR and RT-PCR analysis revealed that the expression of classical UPR chaperone genes was not altered by overexpression of APP.Interestingly, the induction of the ER stress-responsive pro-apoptotic transcription factor CHOP was significantly upregulated in APP-overexpressing cells in comparison to vectortransfected controls. Chelation of intracellular Ca2+ with BAPTA-AM revealed that enhanced CHOP expression after store depletion occured in a Ca2+-dependent manner in APPoverexpressing cells. Prevention of CHOP induction by BAPTA-AM and by RNA interference was also able to abrogate the potentiating effect of APP on thapsigargin-induced apoptosis. Application of the store-operated channel (SOC)-inhibitors SK F96365 and 2-APB downmodulated APP-triggered potentiation of cytosolic Ca2+ levels and apoptosis after treatment with thapsigargin. Our data demonstrate that APP-mediated regulation of ER Ca2+ homeostasis significantly modulates Ca2+ store depletion-induced cell death in a SOC- and CHOP-dependent manner, but independent of the UPR.