BARHL1 Is Downregulated in Alzheimer’s Disease and May Regulate Cognitive Functions through ESR1 and Multiple Pathways
Abstract
:1. Introduction
2. Materials and Methods
2.1. Tissue Samples
2.2. Tissue Microarray and Immunohistochemistry
2.3. Statistical Analysis
2.4. Integrative Bioinformatics Approach
2.4.1. BARHL1 Association with Alzheimer’s Disease
2.4.2. Construction of the BARHL1 Regulatory Circuit
2.4.3. Collection of Alzheimer’s Disease, Parkinson’s Disease and Amyotrophic Lateral Sclerosis Pathway-Specific Genes
2.5. Promoter Analysis
2.6. Protein-Protein Interaction Analysis
2.7. micro RNA Analysis
2.8. Mining the BARHL1 Knockout Mouse Phenotype for Alzheimer’s Disease Symptoms
3. Results and Discussion
3.1. Expression of BARHL1 in the Nervous System and Breast Tumors
3.2. BARHL1 Expression in Alzheimer’s Disease
3.3. Putative Estrogen-BARHL1 Axis in Alzheimer’s Disease
3.4. Estrogen-BARHL1 Network
3.5. Estrogen and BARHL1 Regulate Each Other
3.6. The BARHL1-ESR1 Axis May Regulate a Subset of the Alzheimer’s Disease Pathway
3.7. Role of the BARHL1-ESR1 Network in Alzheimer’s Disease
3.8. Links between the BARHL1-ESR Axis and the Alzheimer’s Disease Pathway
3.9. miRNAs Regulate the BARHL1-ESR1 Axis and the Alzheimer’s Disease Network
3.10. Functions of the BARHL1 and Alzheimer’s Disease Networks Regulating miRNAs
3.11. hsa-mir-18a May Regulate the BARHL1-AD Network and Alzheimer’s Disease Patho-Physiology
3.12. BARHL1 Knockout Mimics Alzheimer’s Disease Symptoms
3.13. Estrogen-ESR1 and Alzheimer’s Disease
4. Conclusions
Supplementary Materials
Acknowledgments
Author Contributions
Conflicts of Interest
Funding
References
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Samples | Types | Number of Samples |
---|---|---|
Breast tumors | HR−/HER2− | 23 |
HR−/HER2+ | 21 | |
HR+/HER2− | 20 | |
HR+/HER2+ | 13 | |
Total | 77 | |
Nervous system tumors | Neuroblastoma | 4 |
Meningioma | 5 | |
Glioma | 4 | |
Peripheral nerve sheath | 3 | |
Total | 16 | |
Neurodegenerative diseases | Alzheimer’s disease | 10 |
Lateral amyotrophic sclerosis | 6 | |
Parkinson’s disease | 1 | |
Total | 17 | |
Total | 110 |
Percentage of Cells (%) | Intensity | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
Type of tissue | 0 | <50 | 50–75 | >75 | 100 | A | B | C | D | |
Control | Hippocampus | 0 | 0 | 0 | 2 | 2 | 0 | 1 | 1 | 2 |
Olfactory bulb | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 2 | 0 | |
Medulla | 1 | 0 | 1 | 1 | 1 | 1 | 0 | 2 | 1 | |
Disease | Alzheimer’s disease | 5 | 3 | 2 | 0 | 0 | 5 | 2 | 2 | 0 |
Parkinson’s disease | 0 | 1 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | |
Lateral amyotrophic sclerosis | 0 | 1 | 2 | 0 | 3 | 0 | 2 | 2 | 2 |
Regulation of BARHL1 and ESR1 | References |
---|---|
BARHL1 upregulates NT-3 (neuro tropin 3 in mouse cerebellum) and thereby regulates the survival of cerebellar granule cells. | Li et al., 2004 [13] |
The BARHL1 promoter has a TRβ binding site, and T3 (thyroid hormone) inhibits the expression of BARHL1. Thus, Brahl1 plays a role in impaired neuro-development caused by hypothyroidism. | Dong et al., 2011 [15] |
ATOH1/MATH1 upregulates BARHL1 in inner ear and central nervous system. | Chellappa et al., 2008 [34] |
ATOH1/MATH1 is repressed by PTF1a. | Pascual et al., 2007 [35] |
TLE1 positively regulates ER-mediated gene expression and cell division. | Holmes et al., 2012 [36] |
Thyroid hormone (T3) phosphorylates and activates ERα. | Meng et al., 2011 [37] |
Estrogen positively regulates THRB in fish. | Filby et al., 2006 [38] |
TTF2 inhibits transactivation of estrogen receptor-alpha in breast cancer cells. | Park et al., 2012 [39] |
Estrogen increased the expression of NTF3, BDNF and NGF proteins. | Bimonte et al., 2004 [40] |
Estrogens increase BDNF levels in the medial prefrontal cortex (PFC) and the hippocampus. | Luine et al., 2013 [41] |
Estradiol induces the BDNF expression and positively regulates dendritic growth, spinogenesis and synaptogenesis in the developing Purkinje cell. | Zhu et al., 2013 [42] |
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Barh, D.; García-Solano, M.E.; Tiwari, S.; Bhattacharya, A.; Jain, N.; Torres-Moreno, D.; Ferri, B.; Silva, A.; Azevedo, V.; Ghosh, P.; et al. BARHL1 Is Downregulated in Alzheimer’s Disease and May Regulate Cognitive Functions through ESR1 and Multiple Pathways. Genes 2017, 8, 245. https://doi.org/10.3390/genes8100245
Barh D, García-Solano ME, Tiwari S, Bhattacharya A, Jain N, Torres-Moreno D, Ferri B, Silva A, Azevedo V, Ghosh P, et al. BARHL1 Is Downregulated in Alzheimer’s Disease and May Regulate Cognitive Functions through ESR1 and Multiple Pathways. Genes. 2017; 8(10):245. https://doi.org/10.3390/genes8100245
Chicago/Turabian StyleBarh, Debmalya, María E. García-Solano, Sandeep Tiwari, Antaripa Bhattacharya, Neha Jain, Daniel Torres-Moreno, Belén Ferri, Artur Silva, Vasco Azevedo, Preetam Ghosh, and et al. 2017. "BARHL1 Is Downregulated in Alzheimer’s Disease and May Regulate Cognitive Functions through ESR1 and Multiple Pathways" Genes 8, no. 10: 245. https://doi.org/10.3390/genes8100245
APA StyleBarh, D., García-Solano, M. E., Tiwari, S., Bhattacharya, A., Jain, N., Torres-Moreno, D., Ferri, B., Silva, A., Azevedo, V., Ghosh, P., Blum, K., Conesa-Zamora, P., & Perry, G. (2017). BARHL1 Is Downregulated in Alzheimer’s Disease and May Regulate Cognitive Functions through ESR1 and Multiple Pathways. Genes, 8(10), 245. https://doi.org/10.3390/genes8100245