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Open AccessArticle

BARHL1 Is Downregulated in Alzheimer’s Disease and May Regulate Cognitive Functions through ESR1 and Multiple Pathways

Centre for Genomics and Applied Gene Technology, Institute of Integrative Omics and Applied Biotechnology, Nonakuri, Purba Medinipur, West Bengal 721172, India
Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG 31270-901, Brazil
Department of Pathology, Santa Lucía General University Hospital (HGUSL), C/Mezquita s/n, 30202 Cartagena, Spain
Catholic University of Murcia (UCAM), 30107 Murcia, Spain
Department of Pathology, Virgen Arrixaca University Hospital (HUVA), Ctra. Madrid Cartagena sn, 30120 El Palmar, Spain
Instituto de Ciências Biológicas, Universidade Federal do Pará, Rua Augusto Corrêa, 01-Guamá, Belém, PA 66075-110, Brazil
Department of Computer Science, Virginia Commonwealth University, Richmond, VA 23284, USA
Department of Psychiatry & McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL 32610, USA
UTSA Neurosciences Institute and Department of Biology, University of Texas at San Antonio, San Antonio, TX 78249, USA
Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
Author to whom correspondence should be addressed.
Genes 2017, 8(10), 245;
Received: 7 August 2017 / Revised: 13 September 2017 / Accepted: 20 September 2017 / Published: 28 September 2017
(This article belongs to the Special Issue Non-coding RNAs)
The Transcription factor BarH like homeobox 1 (BARHL1) is overexpressed in medulloblastoma and plays a role in neurogenesis. However, much about the BARHL1 regulatory networks and their functions in neurodegenerative and neoplastic disorders is not yet known. In this study, using a tissue microarray (TMA), we report for the first time that BARHL1 is downregulated in hormone-negative breast cancers and Alzheimer’s disease (AD). Furthermore, using an integrative bioinformatics approach and mining knockout mouse data, we show that: (i) BARHL1 and Estrogen Receptor 1 (ESR1) may constitute a network that regulates Neurotrophin 3 (NTF3)- and Brain Derived Neurotrophic Factor (BDNF)-mediated neurogenesis and neural survival; (ii) this is probably linked to AD pathways affecting aberrant post-translational modifications including SUMOylation and ubiquitination; (iii) the BARHL1-ESR1 network possibly regulates β-amyloid metabolism and memory; and (iv) hsa-mir-18a, having common key targets in the BARHL1-ESR1 network and AD pathway, may modulate neuron death, reduce β-amyloid processing and might also be involved in hearing and cognitive decline associated with AD. We have also hypothesized why estrogen replacement therapy improves AD condition. In addition, we have provided a feasible new mechanism to explain the abnormal function of mossy fibers and cerebellar granule cells related to memory and cognitive decline in AD apart from the Tau and amyloid pathogenesis through our BARHL1-ESR1 axis. View Full-Text
Keywords: Alzheimer’s disease; bioinformatics; estrogen; microRNA; signaling Alzheimer’s disease; bioinformatics; estrogen; microRNA; signaling
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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.; Blum, K.; Conesa-Zamora, P.; Perry, G. BARHL1 Is Downregulated in Alzheimer’s Disease and May Regulate Cognitive Functions through ESR1 and Multiple Pathways. Genes 2017, 8, 245.

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