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

Abstract

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.

Characterization of the 5′ Regulatory Region of the Human RGS4 Gene In Vitro

“…BARHL1 was detected overexpressing in medulloblastoma and played an important role in neurogenesis. BARHL1 was downregulated in Alzheimer's Disease and other psychiatric disorders [26]. The changing binding of these transcription factors by mutation of rs6678136 might induced psychiatric disorders.…”

Expression of a Barhl1a reporter in subsets of retinal ganglion cells and commissural neurons of the developing zebrafish brain

“…Barhl genes have a crucial role in the control of neuronal subtype acquisition and maintenance during development and in the adult 1,2,5,6,8,14,54 . Loss of Barhl2 protein in the postnatal mammalian retina causes programmed cell death of more than 50% of RGCs 13 .…”

“…BarH-like homeodomain (BARHL) transcription factors play crucial roles in the control of neural cell fate specification, migration, subtype identity acquisition and survival during development of the retina and the brain [1][2][3][4][5][6][7] . Studies have also implicated Barhl in neurodegenerative and neoplastic disorders 8,9 . In Xenopus and mouse, barhl2 appears to be the only family member expressed in the retina 10,11 .…”

Neurotrophin-3 Promotes the Neuronal Differentiation of BMSCs and Improves Cognitive Function in a Rat Model of Alzheimer's Disease

“…Moreover, previous research has suggested that the transplantation of BMSCs overexpressing NT-3 could promote recovery of locomotor function and nerve regeneration in a rat model of spinal cord injury (Wang et al, 2014 ). Recent study showed that NT-3 probably binds to the Brain Derived Neurotrophic Factor (BDNF) and jointly regulate neurogenesis and neural survival (Barh et al, 2017 ). Based on the above research, we speculated that the transplantation of BMSCs modified with the gene for NT-3 could have an impact on nerve regeneration and recovery of cognitive function that might be relevant to the treatment of AD.…”