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.

Keywords: Alzheimer’s disease; bioinformatics; estrogen; microRNA; signaling.

Figure 1

BarH like homeobox 1 (BARHL1) expression in normal and neoplastic specimens from the nervous system. (A) Staining in brain cortex. (B) Cerebellum showing a strong positive expression in granular layer cells (note: the absence of expression in Purkinje cells, indicated by red lines). Specimens from glioma (C), meningioma (D), neuroblastoma (E) and malignant peripheral nerve sheath tumors (F) showing strong positivity for BARHL1 expression. ×20 original magnifications.

Figure 2

BARHL1 expression in normal and neoplastic breast tissue. (A) Ductal epithelial and basal cells showing positive staining, as well as stromal cells. (B) Positive staining for a lobular breast carcinoma. (C) Negative expression in a ductal poorly-differentiated breast carcinoma. (D) Well-differentiated breast carcinoma. Note: cytoplasmic apical lumen staining. ×20 original magnifications.

Figure 3

The estrogen-BARHL1 network (see the text for detail). The solid arrow indicates activation/positive regulation; T denotes inhibition; and the dotted arrow designates newly-suggested regulatory networks based on our analysis. TH: thyroid hormone; THRB: thyroid hormone receptor beta; ATOH1: atonal BHLH transcription factor 1; PTF1a: pancreas specific transcription factor 1a; NTF3: neurotrophin 3; BDNF: brain-derived neurotrophic factor; TTF2: transcription termination factor 2; Estrogen/ER/ESR1: estrogen/estrogen receptor/estrogen receptor 1; TLE1: transducin like enhancer of split 1.

Figure 4

(A) ESR1 binding sites in the BARHL1 promoter and (B) BARHL1 binding sites in the ESR1 promoter. The green dots show V$EREF matrix family binding sites at BARHL1 promoter and blue dots indicate the V$HOMF matrix family binding sites at ESR1 promoter. The red arrows indicate the transcription start sites.

Figure 5

Key linkers (UBC, SUMO1, SUMO2, HMGB1 and TLE2) between the BARHL1-ESR1 axis and the Alzheimer’s Disease (AD) pathway.