BIN1 Research Articles

Genetic Ancestry and Accumulation of BIN1 Gene Risk Alleles Associated to Alzheimer’s Disease in Latin American Populations

Genetic Ancestry and Accumulation of BIN1 Gene Risk Alleles Associated to Alzheimer’s Disease in Latin American Populations

Unveiling Gene Interactions in Alzheimer's Disease by Integrating Genetic and Epigenetic Data with a Network-Based Approach.

Alzheimer's Disease (AD) is a complex disease and the leading cause of dementia in older people. We aimed to uncover aspects of AD's pathogenesis that may contribute to drug repurposing efforts by integrating DNA methylation and genetic data. Implementing the network-based tool, a dense module search of genome-wide association studies (dmGWAS), we integrated a large-scale GWAS dataset with DNA methylation data to identify gene network modules associated with AD. Our analysis yielded 286 significant gene network modules. Notably, the foremost module included the BIN1 gene, showing the largest GWAS signal, and the GNAS gene, the most significantly hypermethylated. We conducted Web-based Cell-type-Specific Enrichment Analysis (WebCSEA) on genes within the top 10% of dmGWAS modules, highlighting monocyte as the most significant cell type (p < 5 × 10-12). Functional enrichment analysis revealed Gene Ontology Biological Process terms relevant to AD pathology (adjusted p < 0.05). Additionally, drug target enrichment identified five FDA-approved targets (p-value = 0.03) for further research. In summary, dmGWAS integration of genetic and epigenetic signals unveiled new gene interactions related to AD, offering promising avenues for future studies.

Alzheimer’s disease risk gene BIN1 modulates neural network activity through the regulation of L‐type calcium channel expression in human induced neurons

AbstractBackgroundBridging Integrator 1 (BIN1) is the second most important Alzheimer’s disease (AD) risk gene after APOE, but its physiological roles and contribution to brain pathology are largely elusive. In this work, we tackled the short‐ and long‐term effects of BIN1 deletion in human induced neurons (hiNs).MethodWe generated isogenic BIN1 WT, KO and HET human induced pluripotent stem cells (hiPSCs), which were differentiated into hiNs grown in 2D and 3D (cerebral organoids) cultures. We also developed a novel protocol for the generation of highly pure glutamatergic neuron cultures, allowing the study of cell‐autonomous roles of BIN1. Using these three different systems, we probed neuronal electrical activity using MEA electrophysiology and gene expression alterations in individual cell types using snRNA‐seq.ResultWe show that BIN1 depletion leads to specific transcriptional alterations in glutamatergic neurons involving mainly genes associated with calcium homeostasis, ion transport and synapse function. We also show that BIN1 regulates calcium transients and neuronal electrical activity through interaction with the L‐type voltage‐gated calcium channel Cav1.2 and regulation of activity‐dependent internalization of this channel. Treatment with the Cav1.2 antagonist nifedipine partly rescues neuronal electrical and gene expression alterations in BIN1 knockout hiNs.ConclusionOur results indicate that BIN1 loss‐of‐function impairs calcium homeostasis at least in glutamatergic neurons, potentially contributing to the transcriptional changes and neural network dysfunctions observed in AD.

MAJIQlopedia: an encyclopedia of RNA splicing variations in human tissues and cancer.

Quantification of RNA splicing variations based on RNA-Sequencing can reveal tissue- and disease-specific splicing patterns. To study such splicing variations, we introduce MAJIQlopedia, an encyclopedia of splicing variations that encompasses 86 human tissues and 41 cancer datasets. MAJIQlopedia reports annotated and unannotated splicing events for a total of 486175 alternative splice junctions in normal tissues and 338317 alternative splice junctions in cancer. This database, available at https://majiq.biociphers.org/majiqlopedia/, includes a user-friendly interface that provides graphical representations of junction usage quantification for each junction across all tissue or cancer types. To demonstrate case usage of MAJIQlopedia, we review splicing variations in genes WT1, MAPT and BIN1, which all have known tissue or cancer-specific splicing variations. We also use MAJIQlopedia to highlight novel splicing variations in FDX1 and MEGF9 in normal tissues, and we uncover a novel exon inclusion event in RPS6KA6 that only occurs in two cancer types. Users can download the database, request the addition of data to the webtool, or install a MAJIQlopedia server to integrate proprietary data. MAJIQlopedia can serve as a reference database for researchers seeking to understand what splicing variations exist in genes of interest, and those looking to understand tissue- or cancer-specific splice isoform usage.

Gut-brain connections in neurodegenerative disease: immunotherapeutic targeting of Bin1 in inflammatory bowel disease and Alzheimer's disease.

Longer lifespan produces risks of age-associated neurodegenerative disorders such as Alzheimer's disease (AD), which is characterized by declines in memory and cognitive function. The pathogenic causes of AD are thought to reflect a progressive aggregation in the brain of amyloid plaques composed of beta-amyloid (Aß) peptides and neurofibrillary tangles composed of phosphorylated tau protein. Recently, long-standing investigations of the Aß disease hypothesis gained support via a passive immunotherapy targeting soluble Aß protein. Tau-targeting approaches using antibodies are also being pursued as a therapeutic approach to AD. In genome-wide association studies, the disease modifier gene Bin1 has been identified as a top risk factor for late-onset AD in human populations, with recent studies suggesting that Bin1 binds tau and influences its extracellular deposition. Interestingly, before AD emerges in the brain, tau levels rise in the colon, where Bin1-a modifier of tissue barrier function and inflammation-acts to promote inflammatory bowel disease (IBD). This connection is provocative given clinical evidence of gut-brain communication in age-associated neurodegenerative disorders, including AD. In this review, we discuss a Bin1-targeting passive immunotherapy developed in our laboratory to treat IBD that may offer a strategy to indirectly reduce tau deposition and limit AD onset or progression.

Abstract A008: Elucidating the effects of the Alzheimer's disease associated gene BIN1 on cancer tumorigenesis

Abstract Purpose- BIN1 is in deleted in ~5% of all prostate cancer (PC) patients and interestingly is highly enriched in the Speckle-type POZ protein (SPOP) mutant subclass (15%) of PC. BIN1 was originally identified as a repressor of cMYC activity and our lab has shown that patients with SPOPmut;MYChigh PC have worse clinical outcomes. Our observation of BIN1 deletion in the SPOP mutant subclass leads us to hypothesize that BIN1 deletion leads to enhanced AR signaling and more aggressive PC. Experimental Procedures- We analyzed baseline protein and mRNA levels of BIN1 in 13 PC cell lines via quantitative polymerase chain reaction (qPCR) and immunoblot. To understand the role of BIN1 in PC cells, we overexpressed BIN1 and evaluated changes in cell proliferation, migration, and AR target gene expression. To elucidate the role of BIN1 in vivo prostate development, we also generated a prostate-specific knockout of BIN1 and investigated changes in prostate development and AR signaling axis over time in this mouse model. Results- Our results show that none of the 13 PC cell lines analyzed had strong protein expression at baseline, but all had detectable mRNA levels. Interestingly, the three cell lines with the highest mRNA expression were AR negative (DU-145), AR independent (LN95) or castration resistant (MDVR). We also saw a decrease in downstream AR target genes (KLK3 and NKX3.1) measured using qPCR after BIN1 overexpression in 22Rv1 cells. We further corroborated this finding by measuring KLK3 expression using a KLK3-luc reporter assay after BIN1 overexpression. BIN1 overexpression also reduced invasive activity of 22Rv1 measured using a Matrigel invasion assay system. Since BIN1 deletion was enriched in SPOP mutant PC clinical data, we evaluated changes in cell proliferation in the wildtype and mutant SPOP cell lines with and without BIN1OE and found that BIN1OEhindered growth of SPOP mutant PC cells. Analysis of the TCGA primary PC dataset illustrate that PC patients harboring BIN1 deletion had higher AR activity compared to PC patients expressing wildtype BIN1. Importantly, mice with prostate specific BIN1 deletion had larger prostate mass at 2 months of age compared to age matched controls and several mice at the 6&amp;9 month had severely enlarged prostates. Conclusion- Our findings show for the first time that BIN1 functions as an inhibitor of the AR signaling axis and deletion of BIN1 leads to higher levels of AR signaling. We also show that BIN1 deletion in mice affects prostate development and leads to enlarged prostates. These novel findings illustrate the clinical significance of BIN1 deletion in PC patients and highlights the AR-signaling axis as a potential target for PC patients with BIN1 deletion Citation Format: Collin McColl, Darlene Skapura, Elisa Echartea, Jenny Deng, Cristian Coarfa, Salma Kaochar, Brian Simons, Aleksandra Rusin. Elucidating the effects of the Alzheimer's disease associated gene BIN1 on cancer tumorigenesis [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A008.

The Relationship Between Bridging Integrator 1 Gene Polymorphism and Susceptibility to Alzheimer’s Disease

Background: Alzheimer’s Disease (AD) is the most common type of dementia. The role of genetic factors in AD development remains non-demonstrated. Objectives: In this study, we aimed to investigate the association between one of the BIN1 gene’s single-nucleotide polymorphisms (SNP) rs744373 and Late-Onset Alzheimer’s Disease (LOAD) in an Iranian population in Guilan Province. Materials &amp; Methods: In this case-control study, 110 patients with LOAD and 110 unrelated healthy controls were recruited. Polymerase chain reaction-restriction length polymorphism (PCRRFLP) was performed for genotyping the BIN1 gene’s SNP rs744373. Electrophoresis was thereafter conducted using agarose gel and DNA-safe stain, and the gels were visualized under an Ultraviolet (UV) trans-illuminator. The allelic and genotypic frequencies were determined. Results: The frequency of allele T (Wild-type allele) in the control and the LOAD groups was 70.9% (n=159) and 58.6% (n=129), respectively (P=0.007). The frequency of allele C in the LOAD group (41.4%) (n=91) was significantly higher than that of the control group (29.1%) (n=64) (P=0.007). BIN’s homozygous genotype (CC) frequency was significantly higher in the LOAD group than in the control group (P=0.043). Conclusion: The rs744373 SNP of the BIN1 gene is significantly associated with the risk of developing AD in the studied population.

NQO1 regulates expression and alternative splicing of apoptotic genes associated with Alzheimer's disease in PC12 cells.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory loss and cognitive dysfunction. Quinone oxidoreductase 1 (NQO1) is an antioxidant enzyme that plays an important role in controlling cellular redox state, whose expression is altered in the brain tissues of AD patients. In addition to its traditional antioxidant effects, NQO1 also acts as a multifunctional RNA-binding protein involved in posttranscriptional regulation. Whether the RNA-binding activity of NQO1 influences AD pathology has not been investigated yet. The RNA-binding functions of NQO1 in rat pheochromocytoma (PC12) cells were investigated using siRNA knockdown followed by total RNA sequencing. Reverse transcription quantitative polymerase chain reaction was performed to explore the impact of NQO1 on the transcription and alternative splicing of apoptotic genes. NQO1 knockdown led to a significant increase in cellular apoptosis. Genes involved in certain apoptosis pathways, such as positive regulation of apoptotic processes and mitogen-activated protein kinase signaling, were under global transcriptional and alternative splicing regulation. NQO1 regulated the transcription of apoptotic genes Cryab, Lgmn, Ngf, Apoe, Brd7, and Stat3, as well as the alternative splicing of apoptotic genes BIN1, Picalm, and Fyn. Our findings suggest that NQO1 participates in the pathology of AD by regulating the expression and alternative splicing of the genes involved in apoptosis. These results extend our understanding of NQO1 in apoptotic pathways at the posttranscriptional level in AD.

Multiple gene variants linked to Alzheimer's-type clinical dementia via GWAS are also associated with non-Alzheimer's neuropathologic entities

The classic pathologic hallmarks of Alzheimer's disease (AD) are amyloid plaques and neurofibrillary tangles (AD neuropathologic changes, or ADNC). However, brains from individuals clinically diagnosed with “AD-type” (amnestic) dementia usually harbor heterogeneous neuropathologies in addition to, or other than, ADNC. We hypothesized that some AD-type dementia associated genetic single nucleotide variants (SNVs) identified from large genomewide association studies (GWAS) were associated with non-ADNC neuropathologies. To test this hypothesis, we analyzed data from multiple studies with available genotype and neuropathologic phenotype information. Clinical AD/dementia risk alleles of interest were derived from the very large GWAS by Bellenguez et al. (2022) who reported 83 clinical AD/dementia-linked SNVs in addition to the APOE risk alleles. To query the pathologic phenotypes associated with variation of those SNVs, National Alzheimer's disease Coordinating Center (NACC) neuropathologic data were linked to AD Sequencing Project (ADSP) and AD Genomics Consortium (ADGC) data. Separate data were obtained from the harmonized Religious Orders Study and the Rush Memory and Aging Project (ROSMAP). A total of 4811 European participants had at least ADNC neuropathology data and also genotype data available; data were meta-analyzed across cohorts. As expected, a subset of dementia-associated SNVs were associated with ADNC risk in Europeans—e.g., BIN1, PICALM, CR1, MME, and COX7C. Other gene variants linked to (clinical) AD dementia were associated with non-ADNC pathologies. For example, the associations of GRN and TMEM106B SNVs with limbic-predominant age-related TDP-43 neuropathologic changes (LATE-NC) were replicated. In addition, SNVs in TNIP1 and WNT3 previously reported as AD-related were instead associated with hippocampal sclerosis pathology. Some genotype/neuropathology association trends were not statistically significant at P < 0.05 after correcting for multiple testing, but were intriguing. For example, variants in SORL1 and TPCN1 showed trends for association with LATE-NC whereas Lewy body pathology trended toward association with USP6NL and BIN1 gene variants. A smaller cohort of non-European subjects (n = 273, approximately one-half of whom were African-Americans) provided the basis for additional exploratory analyses. Overall, these findings were consistent with the hypothesis that some genetic variants linked to AD dementia risk exert their affect by influencing non-ADNC neuropathologies.

Transient modification of macrophages for activation their pro‐inflammatory functions

Macrophages are innate immune cells that play an important role in both physiological and pathological conditions. According to the concept of binary polarization, there are two the most polar states of macrophages: pro‐inflammatory and anti‐inflammatory macrophages. We proposed that targeted programming of macrophages derived from the specific monocyte subpopulation is perspective strategy for activation their inflammation properties that could be used in therapy of cancer or endometriosis. This work is devoted to the study of the effect of Indoleamine 2,3‐dioxygenase 1 (IDO1) and its inhibitor BIN1 on the shift in the polarization of macrophages into a pro‐inflammatory phenotype. We used magnetic sorting, differentiation, and further pro‐inflammatory polarization of CD14+ monocytes from the blood of healthy donors. We obtained data on the transcriptome and proteome and carried out a bioinformatic analysis to identify the most significant differences between two groups of cells – naive and pro‐inflammatory macrophages. IDO1 has been identified as an enzyme with immunomodulatory functions and is also involved in the catabolism of the essential amino acid L‐tryptophan. This enzyme is expressed in macrophages and its expression is induced by pro‐inflammatory cytokines. It was shown that the BIN1 protein is an inhibitor of IDO1 and can inhibit the growth of cancer cells. It was shown that upon the polarization of macrophages towards the pro‐inflammatory phenotype by LPS addition, the expression of IDO1 increases, while the expression of BIN1 decreases (p &lt;0.05). To reveal the influence of the IDO1 and BIN1 genes on the shift of the polarization of macrophages towards the M1 phenotype, we decided to carry out knockdown by using siRNAs on the primary line of CD14+‐derived macrophages. The efficiency of transfection was assessed at different concentrations of siRNA ranged from 30 to 80%, but high concentrations of siRNA led to non‐specific activation of pro‐inflammatory phenotype. Expression analysis confirmed the silencing of the genes IDO1 and BIN1 using 5 nM siRNA. It was shown that knockdown of IDO1 and BIN1 leads to increased expression of pro‐inflammatory genes (CCR7 and TNFa) and decreased the level of anti‐inflammatory interleukin 10. Also, co‐cultivation CD14+ macrophages after knockdown of genes IDO1 and BIN1 didn’t influent on macrophage’s phagocytic functions. The proposed study has a scientific novelty since for the first time a transient modification of the primary line of macrophages from blood CD14 + was carried out and the influence of IDO1 and BIN1 on the activation of the pro‐ or anti‐inflammatory phenotype was shown. Directed programming of macrophages is a new and rapidly developing field.

Link of BIN1, CLU, and IDE Gene Polymorphisms with the Susceptibility of Alzheimer's Disease: Evidence from a Meta-analysis.

Alzheimer's disease (AD) is the most common form of neurodegenerative disorder. The association of BIN1, CLU, and IDE genetic polymorphisms with AD risk have been evaluated overtimes that produced conflicting outcomes. We performed this meta-analysis to investigate the contribution of BIN1 (rs744373 and rs7561528), CLU (rs11136000 and rs9331888), and IDE (rs1887922) polymorphisms to AD risk. From a systemic literature search up to July 15, 2021, we included 25 studies with rs744373, 16 studies with rs7561528, 37 studies with rs11136000, 16 studies with rs9331888, and 4 studies with rs1887922. To analyze the correlation, we constructed seven genetic models that used odds ratio and 95% confidence intervals. We used RevMan 5.4 for meta-analysis. Our study suggests that BIN1 rs744373 is associated with a significantly increased risk of AD in five genetic models (OR>1). Again, CLU rs11136000 showed reduced association in all genetic models (OR<1). CLU rs9331888 revealed an increased association in two models (OR>1). The IDE rs1887922 showed significantly increased risk in four models (OR>1). From subgroup analysis, a significantly increased risk of AD was observed in Caucasians and Asians for BIN1 rs744373. Again, BIN1 rs7561528 showed a significantly enhanced risk of AD only in Caucasians. CLU rs11136000 showed significantly reduced risk in Caucasians but rs9331888 showed increased risk in the same ethnicity. Our meta-analysis confirms the association of BIN1 rs744373, CLU rs9331888, and IDE rs1887922 polymorphisms with an increased risk of AD, especially in Caucasians. Again, CLU rs11136000 is associated with reduced AD risk in the overall population and Caucasians.

Association of Bridging Integrator 1 Gene Polymorphism with Susceptibility to Alzheimer’s Disease

Background: Alzheimer's disease (AD) is the most common type of dementia. The role of genetic factors in the development of AD has not been demonstrated yet. Objectives In this study, our aim was to investigate the association between one of the BIN1 gene’s single-nucleotide polymorphism (SNP( (rs744373) and late-onset Alzheimer's disease (LOAD) in an Iranian population in the Guilan province. Materials &amp; Methods: In this case-control study, 110 patients with LOAD, and 110 unrelated healthy controls were recruited. Polymerase chain reaction-restriction length polymorphism (PCR-RFLP) was performed for genotyping BIN1 gene’s SNP (rs744373). Electrophoresis was there after carried out using agarose gel and DNA safe stain and the gels were visualized under an ultraviolet (UV) trans-illuminator. The allelic and genotypic frequencies were determined. Results: The frequency of allele T (Wild-type allele) in the control and the LOAD groups was 70.9% (n = 159) and 58.6% (n = 129), respectively (p = 0.007). The frequency of allele C in the LOAD group (41.4%) (n = 91) was significantly higher than that of the control group (29.1%) (n=64) (p=0.007). Frequency of homozygous genotype (CC) of BIN was significantly higher in the LOAD group than in the control group (p = 0.043). Conclusion: rs744373 SNP of BIN1 gene is significantly associated with the risk of developing AD in the studied population.

DIET AND ITS MICROENVIRONMENT INFLUENCE THE HEALTH OF COLON

Abstract Ulcerative colitis (UC) is an autoimmune chronic inflammatory disease of the large intestine that greatly increases risks of colorectal cancer. UC is an idiopathic inflammatory disorder of the colonic mucosa, which starts in the rectum and generally extends proximally in a continuous manner through part of, or the entire, colon. A Western diet, smoking, alcohol abuse, altered circadian rhythm and a dysbiotic microbiome is thought to induce UC. However, it is still not completely understood the factors in the diet that triggers UC. Identification of the factors associated with the diet that induce UC will lead to healthier lifestyle that prevents UC. In animal models we show that standard diet and diet rich in fiber positively influenced the health of the colon. A high fat high protein diet negatively regulated the health of the colon. A high fat high protein diet caused obesity in animals, paradoxically it also reduced the colon length significantly in these animals. Animals feeding on a high fat high protein had no energy in the fecal pellet demonstrating peinosis [hunger-like-condition; peina (Greek) hunger; osis (Greek) condition] of the colon. A high fat high protein diet also induced peripheral neuropathy in animals; whereas animals on a high fiber diet was healthy and had longer colon and no peripheral neuropathy. Bacteria of the family Erysipelotrichaceae that is related to inflammation-related disorders of the gastrointestinal tract is also high in animals fed with a high fat high protein diet; these animals also had low levels of valeric acid and propionic acid in the colon. Overall, a high fat high protein diet negatively impacts the health of the colon due to poor energy metabolism and its associated dysbiotic microbiome and metabolome. Currently, anti-inflammatory drugs and immune suppressors are prescribed for UC treatment, side-effects and the risk of opportunistic infections limit the quality of treatment. Hence, there is a need for a new class of biologics for efficient UC treatment. Bin1 is a risk factor in UC as determined by the increase in Bin1 expression in the colon of UC patients. In animal models, we showed that attenuation of BIN1 gene protected against UC. We have developed an innovative therapeutic strategy to treat UC that acts by correcting the leaky colonic epithelial barrier function that drives chronic inflammation in this setting. Specifically, we recently showed that administration of our anti-Bin1 monoclonal antibody (Bin1 mAb 99D) is sufficient to mimic the effect of genetic downregulation of Bin1 to preserve the normal colonic mucosa in an established mouse model of UC, in comparison to control-treated mice which exhibited severe lesions and inflammatory cell influx throughout the mucosa. A diet that positively influence the colon may be beneficial during immunotherapeutic treatment of ulcerative colitis.

The impact of Alzheimer's disease susceptibility loci on lateral ventricular surface morphology in older adults.

The enlargement of ventricular volume is a general trend in the elderly, especially in patients with Alzheimer's disease (AD). Multiple susceptibility loci have been reported to have an increased risk for AD and the morphology of brain structures are affected by the variations in the risk loci. Therefore, we hypothesized that genes contributed significantly to the ventricular surface, and the changes of ventricular surface were associated with the impairment of cognitive functions. After the quality controls (QC) and genotyping, a lateral ventricular segmentation method was employed to obtain the surface features of lateral ventricle. We evaluated the influence of 18 selected AD susceptibility loci on both volume and surface morphology across 410 subjects from Alzheimer's Disease Neuroimaging Initiative (ADNI). Correlations were conducted between radial distance (RD) and Montreal Cognitive Assessment (MoCA) subscales. Only the C allele at the rs744373 loci in BIN1 gene significantly accelerated the atrophy of lateral ventricle, including the anterior horn, body, and temporal horn of left lateral ventricle. No significant effect on lateral ventricle was found at other loci. Our results revealed that most regions of the bilateral ventricular surface were significantly negatively correlated with cognitive scores, particularly in delayed recall. Besides, small areas of surface were negatively correlated with language, orientation, and visuospatial scores. Together, our results indicated that the genetic variation affected the localized areas of lateral ventricular surface, and supported that lateral ventricle was an important brain structure associated with cognition in the elderly.

Alzheimer's Disease Risk Gene BIN1 Modulates Neural Network Activity Through the Regulation of L-Type Calcium Channel Expression in Human Induced Neurons

Alzheimer's Disease Risk Gene BIN1 Modulates Neural Network Activity Through the Regulation of L-Type Calcium Channel Expression in Human Induced Neurons

New Synthetic Lethality Re-Sensitizing Platinum-Refractory Cancer Cells to Cisplatin In Vitro: The Rationale to Co-Use PARP and ATM Inhibitors.

The pro-apoptotic tumor suppressor BIN1 inhibits the activities of the neoplastic transcription factor MYC, poly (ADP-ribose) polymerase-1 (PARP1), and ATM Ser/Thr kinase (ATM) by separate mechanisms. Although BIN1 deficits increase cancer-cell resistance to DNA-damaging chemotherapeutics, such as cisplatin, it is not fully understood when BIN1 deficiency occurs and how it provokes cisplatin resistance. Here, we report that the coordinated actions of MYC, PARP1, and ATM assist cancer cells in acquiring cisplatin resistance by BIN1 deficits. Forced BIN1 depletion compromised cisplatin sensitivity irrespective of Ser15-phosphorylated, pro-apoptotic TP53 tumor suppressor. The BIN1 deficit facilitated ATM to phosphorylate the DNA-damage-response (DDR) effectors, including MDC1. Consequently, another DDR protein, RNF8, bound to ATM-phosphorylated MDC1 and protected MDC1 from caspase-3-dependent proteolytic cleavage to hinder cisplatin sensitivity. Of note, long-term and repeated exposure to cisplatin naturally recapitulated the BIN1 loss and accompanying RNF8-dependent cisplatin resistance. Simultaneously, endogenous MYC was remarkably activated by PARP1, thereby repressing the BIN1 promoter, whereas PARP inhibition abolished the hyperactivated MYC-dependent BIN1 suppression and restored cisplatin sensitivity. Since the BIN1 gene rarely mutates in human cancers, our results suggest that simultaneous inhibition of PARP1 and ATM provokes a new BRCAness-independent synthetic lethal effect and ultimately re-establishes cisplatin sensitivity even in platinum-refractory cancer cells.

Role of the late-onset Alzheimer's disease risk genes bin1 and ptk2b in the hyperexcitability of hiPSC-derived neurons.

The BIN1 (Bridging Integrator-1) gene is the second most important Alzheimer's disease risk gene and has been associated with synaptic transmission defects in animal models. PTK2B (Protein Tyrosine Kinase 2β) is a Ca2+ -activated non-receptor tyrosine kinase, also identified by genome-wide association study (GWAS) as an important AD risk factor, and playing a role in the mouse hippocampal synaptic plasticity. In this work, we aimed at studying the possible effects of BIN1 or PTK2B underexpression in the electrical activity taking advantage of human induced pluripotent stem cell (hiPSC)-derived neurons. To this aim, we are using hiPSCs expressing allelic variants of BIN (BIN1+/+ and BIN1-/-) or PTK2B (PTK2B+/+, PTK2B+/- and PTK2B -/-). Human induced neural progenitor cells (hiNPCs) are generated from these hiPSCs, which are further differentiated into mature neurons and glia. We evaluated the gene expression, cell type composition of cultures, and neuronal electrical activity using western blot, immunocytochemistry, pharmacological assays, and calcium imaging as a readout of the electrical function. Our preliminary data suggest that BIN1 KO decreases proliferation of NPCs. In addition, analyses of calcium imaging recordings show decreased number of active cells although, the active ones show a higher calcium spikes frequency and less synchronization. Furthermore, neuronal activity or PTK2B underexpression impairs the differentiation potential of hiNPCs into neurons. As well, and increased calcium spikes frequency in hiNs. Taken together, our preliminary panel of data suggests that both BIN1 and PTK2B regulate important biological processes involved in neuronal differentiation and electrical maturation. Thus, altered expression of these genes in the AD brain could play a role in neuronal hyperexcitability observed in patients.

Common Pathogenic Mechanisms in Centronuclear and Myotubular Myopathies and Latest Treatment Advances.

Centronuclear myopathies (CNM) are rare congenital disorders characterized by muscle weakness and structural defects including fiber hypotrophy and organelle mispositioning. The main CNM forms are caused by mutations in: the MTM1 gene encoding the phosphoinositide phosphatase myotubularin (myotubular myopathy), the DNM2 gene encoding the mechanoenzyme dynamin 2, the BIN1 gene encoding the membrane curvature sensing amphiphysin 2, and the RYR1 gene encoding the skeletal muscle calcium release channel/ryanodine receptor. MTM1, BIN1, and DNM2 proteins are involved in membrane remodeling and trafficking, while RyR1 directly regulates excitation-contraction coupling (ECC). Several CNM animal models have been generated or identified, which confirm shared pathological anomalies in T-tubule remodeling, ECC, organelle mispositioning, protein homeostasis, neuromuscular junction, and muscle regeneration. Dynamin 2 plays a crucial role in CNM physiopathology and has been validated as a common therapeutic target for three CNM forms. Indeed, the promising results in preclinical models set up the basis for ongoing clinical trials. Another two clinical trials to treat myotubular myopathy by MTM1 gene therapy or tamoxifen repurposing are also ongoing. Here, we review the contribution of the different CNM models to understanding physiopathology and therapy development with a focus on the commonly dysregulated pathways and current therapeutic targets.

Association of Gene Polymorphisms in APOE and BIN1 With Dementia of Alzheimer's Type Susceptibility in Chinese Han Population.

Objectives: Dementia of the Alzheimer's type (DAT) is the most common chronic neurodegenerative disease. At present, the pathogenesis of DAT is not completely clear, and there are no drugs that can cure the disease. Once an individual is diagnosed with DAT, the survival time is only 3 to 9 years. Therefore, there is an urgent need to determine the etiology of DAT and the associated influencing factors to find a breakthrough in the treatment of DAT.Methods: We studied the relationship between polymorphisms in several genes (including BIN1 and APOE) and DAT susceptibility and the effects of sex differences on DAT. Our study included 137 patients with DAT and 509 healthy controls (HCs).Results: The APOE rs429358 polymorphism CC and CT genotypes were associated with an increased risk of DAT in women. We found a significant association between APOE ε4 and DAT. The frequency of the ε4 allele in the DAT group (15.5%) was higher than that in the HC group (8.7%). The BIN1 rs7561528 polymorphism was associated with a decreased risk of DAT in men.Conclusions: APOE gene rs429358 and BIN1 gene 7561528 genes may affect the susceptibility to DAT in a Chinese Han population.

Association between Alzheimer's disease genes and trajectories of cognitive function decline in Han Chinese in Taiwan.

Genetic background has been considered one of the important contributors to the rate of cognitive decline among patients with Alzheimer’s disease (AD). We conducted a 4-year longitudinal follow-up study, recruited 255 AD and 44 mild cognitive impairment (MCI) patients, and used a data-driven trajectory analysis to examine the influence of selected AD risk genes on the age for and the rate of cognitive decline in Han Chinese population. Genotyping of selected single-nucleotide polymorphisms in the APOE, ABCA7, SORL1, BIN1, GAB2, and CD33 genes was conducted, and a Bayesian hierarchical model was fitted to analyze the trajectories of cognitive decline among different genotypes. After adjusting for sex and education years, the APOE ε4 allele was associated with an earlier mean change of −2.39 years in the age at midpoint of cognitive decline, the G allele in ABCA7 rs3764650 was associated with an earlier mean change of −1.75 years, and the T allele in SORL1 rs3737529 was associated with a later mean change of 2.6 years. Additionally, the rate of cognitive decline was associated with the APOE ε4 allele and SORL1 rs3737529. In summary, APOE and SORL1 might be the most important genetic factors related to cognitive decline in Han Chinese population.