A novel neuron-enriched protein SDIM1 is down regulated in Alzheimer's brains and attenuates cell death induced by DNAJB4 over-expression in neuro-progenitor cells
© Lei et al; licensee BioMed Central Ltd. 2011
Received: 16 August 2010
Accepted: 21 January 2011
Published: 21 January 2011
Molecular changes in multiple biological processes contribute to the development of chronic neurodegeneration such as late onset Alzheimer's disease (LOAD). To discover how these changes are reflected at the level of gene expression, we used a subtractive transcription-based amplification of mRNA procedure to identify novel genes that have altered expression levels in the brains of Alzheimer's disease (AD) patients. Among the genes altered in expression level in AD brains was a transcript encoding a novel protein, SDIM1, that contains 146 amino acids, including a typical signal peptide and two transmembrane domains. Here we examined its biochemical properties and putative roles in neuroprotection/neurodegeneration.
QRT-PCR analysis of additional AD and control post-mortem human brains showed that the SDIM1 transcript was indeed significantly down regulated in all AD brains. SDIM1 is more abundant in NT2 neurons than astrocytes and present throughout the cytoplasm and neural processes, but not in the nuclei. In NT2 neurons, it is highly responsive to stress conditions mimicking insults that may cause neurodegeneration in AD brains. For example, SDIM1 was significantly down regulated 2 h after oxygen-glucose deprivation (OGD), though had recovered 16 h later, and also appeared significantly up regulated compared to untreated NT2 neurons. Overexpression of SDIM1 in neuro-progenitor cells improved cells' ability to survive after injurious insults and its downregulation accelerated cell death induced by OGD. Yeast two-hybrid screening and co-immunoprecipitation approaches revealed, both in vitro and in vivo, an interaction between SDIM1 and DNAJB4, a heat shock protein hsp40 homolog, recently known as an enhancer of apoptosis that also interacts with the mu opioid receptor in human brain. Overexpression of DNAJB4 alone significantly reduced cell viability and SDIM1 co-overexpression was capable of attenuating the cell death caused DNAJB4, suggesting that the binding of SDIM1 to DNAJB4 might sequester DNAJB4, thus increasing cell viability.
Taken together, we have identified a small membrane protein, which is down regulated in AD brains and neuronal cells exposed to injurious insults. Its ability to promote survival and its interaction with DNAJB4 suggest that it may play a very specific role in brain cell survival and/or receptor trafficking.
Alzheimer disease (AD) is the most common neurodegenerative disorder, manifesting clinical symptoms of cognitive impairment and dementia, which result from progressive synaptic dysfunction, loss and neuronal cell death. Pathologically, AD is characterized by the deposition of β-amyloid leading to the development of senile plaques and hyperphosphorylated tau protein aggregates within the cortical neurons, forming neurofibrillary tangles (NFTs). Our current understanding of early onset (familial) AD is derived primarily from studies on genes or gene products identified in genetically determined forms. These AD cases exhibit genetic linkage to mutations in presenilin-1 (PS1), presenilin-2 (PS2) and β-amyloid precursor protein (APP) genes . Although these discoveries have been helpful in elucidating the basic molecular pathogenesis of familial AD, they only represent a relatively small fraction of the AD population. The large majority of cases are late onset AD (LOAD), which are genetically heterogeneous and occur sporadically. Several genetic risk factors have been described for LOAD, notably an allelic polymorphism of apolipoprotein E that affects the age of onset , but the precise etiology of LOAD is poorly understood.
Alterations in multiple biological processes contribute to the development of LOAD, some of which correlate with cognitive impairment . Well established brain changes include excessive oxidative stress and insufficient antioxidant defenses, disrupted calcium homeostasis, altered cholesterol synthesis and transport, inappropriate hormonal and growth factor signaling, chronic inflammation, aberrant re-entry of neurons into the cell cycle and, especially, aberrant protein processing, folding and turnover, leading ultimately to senile plaques and NFT formation . Due to the vast extent and complexity of these changes, global gene expression profiling has been adopted as a discovery-based approach to study this idiopathic and multifactorial disease. Although the discovery of concurrent changes in AD brains cannot establish cause and effect, or separate detrimental from compensatory effects, they can generate unique insights and testable hypotheses on processes that may drive brain and cognitive dysfunction.
The most commonly used technology for the assessment of gene expression changes in postmortem AD brains is DNA microarray analysis [5–9]. This approach has allowed relative quantitative assessment of thousands of genes simultaneously, providing clues for new candidate genes not previously associated with AD. However, this method requires prior knowledge of gene sequences and cannot be applied as a discovery tool for novel transcripts. Furthermore, the expression levels of low abundance genes cannot be readily assessed by DNA microarray hybridization, as reliable results are usually obtained only for genes that are expressed in high or moderate levels. We have recently employed a subtractive hybridization and RNA amplification method to enrich and isolate rare and novel transcripts involved in LOAD. Using this approach, we have isolated a number of novel transcripts that are differentially expressed in the brains of AD patients . Among these was a novel sequence, SDIM1, that not only was down regulated in AD brains, but was also very responsive to stress conditions mimicking the injurious insults that may cause neurodegeneration in AD brain.
In the present study, we demonstrate its biochemical properties, tissue/cell type distribution, putative roles in neuronal cells that are exposed to toxic insults causing neurodegeneration, and have explored its relationship with other key proteins in the brain.
SDIM1 is a novel transmembrane protein down regulated in AD brains
Description of brain samples used for qRT-PCR analysis of SDIM1
Moderate senile changes of AD type, dementia
Subdural hematomas, senile changes of AD type
Moderate senile changes of AD type, dementia
Probable AD, according to CERAD, CVD cerebrum, right infarct old
Probable AD, according to CERAD
Probable AD, according to CERAD
Senile dementia of AD type
CERAD classification 2, definite AD
Expression pattern of SDIM1
SDIM1 is highly responsive to stress conditions mimicking injurious insults
Overexpression of SDIM1 protected cells from injurious insults and its downregulation accelerated cell death caused by OGD in neuronal progenitor cells
SDIM1 interacts with a DnaJ-like heat shock protein
SDIM1 attenuates cell death induced by DNAJB4 overexpression
We have isolated a novel neuron-enriched protein, SDIM1, which is down regulated in AD brain tissues. Further study of its expression in NT2 cell model and in mouse primary neurons revealed that this gene was barely detectable in undifferentiated NT2 cells, and is much more abundant in differentiated neurons than astrocytes. Treatments of neuronal cells with OGD and OGD plus 16 h recovery triggered a bi-phasic response of SDIM1 transcript and protein. SDIM1 is down regulated 2 h after OGD, but became highly up-regulated 16 h after re-oxygenation, in surviving neurons. Furthermore, over-expression of SDIM1 in N2a cells protected the cells from apoptosis caused by OGD insults. Conversely, down-regulation of SDIM1 by siRNA alone did not trigger cell death, whereas down-regulation of SDIM1 followed by OGD treatment of the cells caused accelerated cell death. These results suggest that SDIM1 is capable of promoting cell survival and this protective function is induced by signals triggered by stress conditions.
Although analysis of human and mouse tissues indicated that SDIM1 is relatively abundant in muscle, heart and reproductive organs, suggesting that this protein may have a basic housekeeping function under normal physiological conditions, it is the down regulation in AD brains that links SDIM1 to diseased conditions. SDIM1 transcript level is significantly lower in the cortex of AD patients than that of age matched controls. In our cell systems treated with injurious insults, SDIM1 is also down regulated and only becomes up regulated in surviving cells when given a recovery period. These results indicate that the surrounding microenvironment of the AD brain presents a constant stressed condition for brain cells. Neuroinflammation, oxidative stress, ischemia and Aβ deposition could all contribute to the creation of this harmful environment. Based on the siRNA knock down experiments, down regulation of SDIM1 alone is not enough to kill cells. However, when downregulation of SDIM1 in the cells combined with injurious insults caused increased amounts of cell death, suggesting that a decreased level of SDIM1 in the microenvironment of AD brains may likely cause neuronal cell death.
Through yeast two hybrid and co-immunoprecipitation assays we have discovered that SDIM1 interacts with DNAJB4, a member of DNAJ like heat shock protein 40. DNAJ/HSP40 proteins have been characterized as co-chaperones involved in the regulation of HSP70 chaperone activities . DNAJB4 has been recently identified as a novel tumor suppressor of non-small-cell lung cancer (NSCLC) that can inhibit cancer cell cycle progression, proliferation, invasion and tumorigenesis. DNAJB4 expression was lower in tumors than adjacent normal tissues and patients with high DNAJB4 expression tumors had reduced cancer recurrence and longer survival than those with lower expressing tumors . Studies on its regulatory mechanism revealed that DNAJB4 is transcriptionally up regulated via enhancer activator protein-1 (AP-1) binding to promoter Yin Yang-1 (YY1) and the co-activator, p300 [14, 15]. Further investigations on the mechanism of action of DNAJB4 on tumor progression, particularly on its role in apoptosis of lung cancer cells exposed to UV stress, has indicated that DNAJB4 promotes UV induced apoptosis through JNK and caspase-3 activation in NSCLC cell line. DNAJB4 is a substrate of caspase-3 and this cleavage of DNAJB4 by caspase-3 is required for UV induced apoptosis in CL1-5 cells stably overexpressing DNAJB4. Consequently, DNAJB4 is reduced in UV exposed cells, and almost completely depleted by the late stage of apoptosis . The results on the role of DNAJB4 in apoptosis obtained in the present study is, in principle, consistent with those obtained from NSCLC cell lines, in that over-expression of DNAJB4 in N2a cells promotes apoptosis. Silencing DNAJB4 decreases apoptosis induced by OGD (Figurs. 8C, 8I,). The difference is that transient over-expression of DNAJB4 alone in N2a cells can trigger apoptosis without any apoptotic inducer. This discrepancy is likely due to the fact that the NSCLC cell over expressing DNAJB4 is a cell line that had passed through a selection procedure for stable, forced-expression of exogenous DNAJB4. Many cells that initially over-express DNAJB4 would undergo apoptosis and might not survive long enough to form stably transfected clones. Further studies are required to identify whether the underlying molecular mechanism of DNAJB4 triggered cell death in neuro-progenitor cells is similar to that in NSCLC cells.
DNAJB4 is identified in the present study as a protein that interacts with a novel neuron-enriched protein SDIM1 that is down regulated in AD brains. However, we did not detect significant changes of DNAJB4 in AD brains. The fact that DNAJB4 protein is quickly depleted in apoptotic neurons and in NSCLC makes it difficult to quantitate whether there exists an initial up regulation of DNAJB4 which triggers the cascade of neurodegeneration in AD brains. The decreased amounts of DNAJB4 in cultured NT2 or primary neurons either during OGD treatment or after the recovery period is also likely due to the depletion of this protein in apoptotic cells. In these cell models, SDIM1 is highly responsive to OGD treatment. It's up regulation in the surviving cell population is highly pronounced, implying a protective function. Over-expression of DNAJB4 triggered an increase of endogenous SDIM1 suggesting that DNAJB4 induced cell death is not due to SDIM1 degradation mediated by DNAJB4; instead, this over-expression can trigger SDIM1 up-regulation, thus protect cells from DNAJB4 induced apoptosis (Figure 8F and 8G). This protective function appears to be independent of OGD treatment, because over-expression of SDIM1 attenuated apoptosis caused by DNAJB4 over-expression without any OGD treatment (Figure 8C). On the other hand, knocking down SDIM1 by siRNA silencing increases cell death induced by OGD (Figure 6E), indicating that SDIM1 also protects cells from apoptosis caused by OGD. Taken together, our data suggest that SDIM1 is a novel protein that possesses protective function against stress induced cell death.
It has been reported that DNAJB4 interacts with the carboxyl tail of human mu opioid receptor in the cell membrane . While the functional relevance of this interaction still remains elusive, since DNAJB4 interacts with HSP70, and the latter is involved in synaptic transmission and regulation, it was speculated that DNAJB4 might work in concert with other HSP proteins to play a role in receptor trafficking.
We have isolated a novel neuron-enriched protein, SDIM1, which is down regulated in AD brains. Further study of its function in neuronal cell models indicates that this protein is protective of neuro-progenitor cells from OGD induced cell death. Its physical interaction with DNAJB4, which is an apoptotic enhancer in NSCLC cells, and its ability to attenuate DNAJB4 mediated apoptosis suggest an anti-apoptotic function of SDIM1. However, further studies are necessary to understand the role of DNAJB4 in brain tissues, especially in the context of AD, and the protective mechanism of SDIM1 under stressed conditions in human brain.
Cell culture and oxygen-glucose deprivation (OGD) treatment
Human embryonal teratocarcinoma Atera2/D1 (NT2) cells (Stratagene, La Jolla, CA), mouse Neuro-2a (N2a) neuroblastoma cells (ATCC CCL-131) and human HEK 293 cells  were cultured in Dulbecco's modified Eagle's medium (Invitrogen, Bethesda, MD) supplemented with 10% fetal calf serum (GCS, Wisent, Inc. St. Bruno, PQ). NT2 cells were differentiated into neurons and astrocytes with all trans-retinoic acid (RA, Sigma, Oakville, ON) according to the method of Pleasure and Lee  as described previously . Mouse primary cortical neurons were prepared from embryonic E15-16 CD1 mice and cultured in neurobasal media for 5-14 days as previously described .
For OGD treatment, NT2 neurons and mouse primary neurons were washed once with glucose-free DMEM, and incubated in glucose-free DMEM with 10% FBS for 2 h in a hypoxic chamber (Forma 1025 Anaerobic Chamber; ThermoForma, Marietta, OH, USA). At the end of the OGD treatment, cells were removed from the chamber and returned to the incubator for 16 h. The same OGD treatment was performed with undifferentiated NT2 and N2a cells except the incubation in OGD conditions was increased to 6 h due to their resistance to OGD treatment. Cell viability for all cell lines was assessed by the Trypan Blue (Sigma, Oakville, ON) exclusion assay. In this procedure, all floating cells were collected from culture media and washing buffer, and then combined with the trypsinized cells. Cells were incubated in the Trypan Blue dye for 5 min. Labelled cells were counted using a hemocytometer.
RNA extraction, real time quantitative RT-PCR (qRT-PCR) and semi-quantitative RT-RCR
RNA extraction, first strand cDNA synthesis, and qRT-PCR analysis were performed as described previously . RNA pools extracted from frontal cortex of postmortem human brain samples described previously  were used for subtractive hybridization and qRT-PCR. Additional brain samples were obtained from the Human Brain and Spinal Fluid Resource Center (, VAMC, Los Angeles, CA), which is sponsored by NINDS/NIMN, National Multiple Sclerosis Society, VA Greater Los Angeles Healthcare System, and Veterans Health Services and Research Administration, Department of Veteran Affairs. To detect the expression level of the SDIM1 transcript in brain tissue and cultured cells, equal amounts of cDNA (2 ng each) were used with the primers: SDIM1F 5' GGGCCATGAACACATCACTTG 3' and SDIM1R 5' TCAGGTCAAAGTTGGCAATGAA 3'. The DNAJB4 transcript was detect by using the primers: DNAJB4F 5' TCTCAAACAAGACCCTCCCA 3' and DNAJB4R 5' ATGGCAGCCCATATCCAATA 3'. PCR was performed using a ABI 7500 FAST Real Time PCR system and reagents according to the manufacturer's instructions. The primers used for semi-quantitative RT-PCR for SDIM1 are: F 5' TCGGTGGGAAGACTGCTTAT 3' and R 5' CGTCTGTCCTGTGACATGGT 3'; for DNAJB4 are: F 5' TGGTTGTACCAAACGGATGA 3' and R 5' ATGGCAGCCCATATCCAATA 3'.
Plasmids, transient transfections and staining
Human cDNA encoding the mature (without the signal peptide) SDIM1 protein was cloned into the pGEX -3X vector (GE Healthcare, Baie d'Urfe Quebec) for GST-SDIM1 fusion protein production. The first amino acid after the signal peptide (position 27) was mutated from "C" to "A" in order to increase the solubility of the recombinant SDIM1 protein in E. coli. Human cDNA encoding full length SDIM1 protein was cloned in the pEGFP-N1 vector (Clontech, Palo Alto, CA, USA) with or without a stop codon added between the C-terminus of SDIM1 and the EGFP sequence (Invitrogen, Burlington, ON) to produce pSDIM1*EGFP, pSDIM1-EGFP respectively. The coding region of the human DNAJB4 cDNA was cloned into the pCMV-Tag1 vector to create a pCMV-DNAJB4-Tag1 construct.
For overexpression analysis, N2a cells were plated in 6-well plates at a density of 0.5 × 106 cells/well, 24 h before transfection. Cells were transfected with 5 μg pCMV-DNAJB4-Tag1 plasmid or pSDIM1*EGFP plasmid and 15 μl lipofectAmine 2000 reagent, or co-transfected with 2.5 μg each of the pSDIM1*EGFP and pCMV-DNAJB4-Tag1 plasmids plus 15 μl lipofectAmine 2000 reagent. Cells were collected for Trypan Blue exclusion assay as well as total RNA and protein extraction 16-24 h after transfection; or treated with OGD for 6 h plus 16 h recovery prior to Trypan blue assay or total RNA and protein extraction. For siRNA silencing, the siRNAs were purchased from GenePgarma (Shanghai GenePgarma Co, Ltd, Shanghai, PRC). Undifferentiated NT2 cells were plated in 12-well plates at a density of 0.25 × 106 cells/well, 24 h before transfection. Cell were transfected with 100 μM mixed human SDIM1 siRNAs containing a pool of two sequences: 5' UUAAACAGAGAUAUAAGUC 3' and 5' UUUAAUAGACCACAAACUC 3' and/or 100 μM mixed human DNAJB4 siRNAs containing three sequences: 5' UUGGAUAGUCUAGCACUUC 3', 5' UUUCUUCAGAAUCUCUACC 3' and 5' UUUCGAGAAAUCUUCAUCC 3' using Dharmafect1 transfection reagent according the manufacturer's instructions (Dharmacon, Thermo Fisher Scientific, Inc). Cells were subjected to 6 h OGD treatment 24 h after transfection and collected for Trypan Blue exclusion assay 16 h after re-oxygenation. For co-immunoprecipitation analysis, HEK 293 cells were plated in 10 cm plates at a density of 2 × 106 cells /plate, 24 h before transfection. Cells were transfected with 15 μg of pEGFPN1 or pSDIM1-EGFP alone, or co-transfected with 7.5 μg each of pSDIM1-EGFP and pCMV-DNAJB4-Tag1 plasmids DNA mixed with 45 μl LipofectAmine 2000 reagent. Cells were collected for total protein extraction 21 h after transfection. For cellular localization of SDIM1, mouse primary cortical neurons were stained (or double-stained) with anti-SDIM1 (dilution1:100 v/v), anti-MAP2 (1:200 v/v dilution, Novus Biologicals, Inc Littleton, CO), or anti-DNAJB4 (1:100 v/v dilution, abcam, Cambridge, MA) antibodies, followed by FITC -conjugated anti-rabbit IgG, rhodomine-conjugated anti-mouse IgG (for MAP2 and DNAJB4). The nuclei were counterstained with DAPI in PBS for 5 min and then mounted in Vectashield mounting medium (Vector laboratories, Burlingame CA, USA). The cells were viewed with a Zeiss Axiovert 200 M fluorescence microscope equipped with a Zeiss AxioCam camera (Zeiss, Midland, ON). The images were captured and analyzed using Zeiss Axiovision 3.1 software.
Antibody production and purification
Custom polyclonal antibody (GenScprit, Piscataway, NJ) was produced using synthetic peptide N'-LGSPLSLWSIKTPS. The immune serum was purified by immunoaffinity purification using recombinant GST-SDIM1 fusion protein. Briefly, purified GST-SDIM1 fusion protein was separated by SDS-PAGE and electro-blotted onto a nitrocellulose membrane. The Ponceau stained membrane portion containing the SDIM1 antigen was excised and subjected to a Western blotting procedure using 2 mL original crude serum. The bound antigen-specific antibody was eluted with 0.1 M Glycine-HCl buffer, pH 2.7. The eluted antibody was neutralized by adding 1/10 volume of 1 M Tris, pH 8.5, concentrated using Amicon Ultra-15 Centrifugal Filter Device (Millipore, Fisher Scientific, Ottawa, ON).
Protein extraction, Western blotting and co-immunoprecipitation
Recombinant GST-SDIM1 fusion protein was purified from Rosetta cells using a glutathione column according to the manufacturer's instruction (GE Healthcare, Baie d'Urfe Quebec). Mouse tissues were frozen in liquid nitrogen and homogenized in RIPA buffer in an electronic homogenizer and then kept on ice for 45 min. The samples were centrifuged at 14,000 xg for 10 min at 4°C to collect the supernatant for total cellular proteins. For total protein extraction from cultured cells, cells were trypsinized and collected by centrifugation. They were washed twice with PBS and lysed with RIPA buffer containing 1X protease Inhibitor cocktail (Roche Diagnostics, Indianapolis, IN). The lysate was vortexed and incubated on ice for 15 min, followed by sonication for 30 sec. In some cases the total cellular protein was freeze-dried and reconstituted in PBS in order to achieve a higher concentration. Western blotting analyses were performed as previously described . Human tissue protein blot was purchased from BioChain Institute, Inc (Hayward, CA, USA). Each lane contains 50 μg of total cellular protein. The blots were probed with the following primary antibodies: Rabbit polyclonal, affinity-purified anti-SDIM1 (1:5000), rabbit polyclonal anti-flag (1:1000, Rockland, Gilbertsville, PA), mouse monoclonal anti-DNAJB4 (1:1000, Abcam, Cambridge, MA), mouse monoclonal anti-EGFP (1:1000, Milipore, Temecula, CA), goat polyclonal anti-GST (1:1000, Amersham Phamacia Biotech, Baie d'Urfe, QC), mouse monoclonal anti-ubiquitin (1:1000) and mouse monoclonal anti-β-actin (1:5000, both Sigma, Oakville, ON), and mouse monoclonal anti-GAPDH (1:10,000 v/v, Milipore, Temecula, CA). The antigens were detected using horseradish peroxidase-conjugated secondary antibodies: anti-mouse IgG (1:5000 v/v), anti-rabbit IgG (1:5000 v/v, both from Jackson ImmunoResearch Laboratories, Inc., West Grove, PA) or anti-goat IgG (1:5000, Sigma, Oakville, ON). The antigen-antibody complexes were visualized by enhanced chemiluminescence using an ECL Plus detection kit (Amersham Phamacia Biotech, Baie d'Urfe, QC).
For the co-immmunoprecipitation assay, flag-tagged DNAJB4 and EGFP-tagged SDIM1 constructs were transiently co-transfected into HEK-293 cells and total cellular proteins were extracted as described above. In another case, purified GST-SDIM1 protein was mixed with cellular proteins extracted from HEK-293 cells transfected with pEGFP-N1 or pSDIM1-EGFP. The immunoprecipitation procedure was as described previously  and precipitated complexes were boiled in protein loading buffer and separated by SDS-PAGE. The presence of SDIM1, DNAJB4, GST-SDIM1, and SDIM1-EGFP in the complex was revealed by Western blotting as described above.
Yeast two-hybrid screening
Human cDNA encoding the full length SDIM1 protein was cloned into the pGBKT7 vector (Clontch, Palo Alto, CA, USA) to generate a chimaeric open reading frame encoding the Gal4 DNA binding domain and SDIM1 protein. This construct was introduced into Saccharomyces cerevisiae strain AH109. A single colony containing cells harboring the pGBKT7-SDIM1 plasmid was then used to provide host cells for screening a human brain cDNA expression library constructed using the pACT2 vector (Clontech, Palo Alto, CA, USA). The protein-protein interaction was first screened by plating the transformants onto SD/-Trp-Leu-His-Ade selection plates. Positive clones were then re-screened for the presence of β-galactosidase activity to eliminate false interactions. Library plasmids harboring SDIM1 interacting proteins were rescued and re-introduced into the pGBKT7/SDIM1-containing host cells to further eliminate false interactions. The identity of the cDNA encoding SDIM1-interacting protein was revealed by DNA sequencing and database searches.
The authors would like to thank Drs Marianna Sikorska and Maria Ribecco for their contribution to the initial construction of human control and AD cDNA libraries. We thank Ms Stephanie Crosbie, Mr. JC Achenbach for their technical assistance, Ms Amy Aylsworth for kindly providing mouse primary neurons, the co-op students Sasha High, Katie Morse for their contribution to this project and Dr. Iain McKinnell for editing this manuscript.
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