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

Debmalya Barh,Artur Silva,Belén Ferri,Daniel Torres-Moreno,Sandeep Tiwari,Neha Jain,Preetam Ghosh,Vasco Azevedo,Antaripa Bhattacharya,Pablo Conesa-Zamora,George Perry,Kenneth Blum,María García-Solano

doi:10.3390/genes8100245

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.

Highlights

Alzheimer’s disease (AD) is one of the “most common forms of neurodegenerative dementia” [1].The global prevalence of AD is as high as 24 million, and in the USA, alone it is approximately5.4 million including a younger-onset AD population of approximately 200,000 [2,3]
BarH like homeobox 1 (BARHL1) first expression was the reported in medulloblastoma
In our neuron cancer samples, BARHL1 was found overexpressed in all samples as compared to their normal counterpart samples, BARHL1 was found overexpressed varied in all samples as compared their tissues, the degree of overexpression depending on the to type ofnormal cancer.counterpart

Summary

Introduction

Alzheimer’s disease (AD) is one of the “most common forms of neurodegenerative dementia” [1].The global prevalence of AD is as high as 24 million, and in the USA, alone it is approximately5.4 million including a younger-onset AD population of approximately 200,000 [2,3]. Alzheimer’s disease (AD) is one of the “most common forms of neurodegenerative dementia” [1]. The global prevalence of AD is as high as 24 million, and in the USA, alone it is approximately. 5.4 million including a younger-onset AD population of approximately 200,000 [2,3]. According to the Alzheimer’s Association, every 68 s, someone develops AD in the USA, which is projected to be one new case of AD every 33 s by 2050 [3]. The deaths due to cardiovascular diseases and cancer have decreased to a certain extent, deaths from AD have increased significantly (66% in the USA) [3]. Development and maintenance of the nervous system requires coordinated actions of multiple transcription factors that may be affected in neurodegenerative disorders like

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