Development is a complex process regulated both by genetic and epigenetic and environmental clues. Recently, long non-coding RNAs (lncRNAs) have emerged as key regulators of gene expression in several tissues including the brain. Altered expression of lncRNAs has been linked to several neurodegenerative, neurodevelopmental and mental disorders. The identification and characterization of lncRNAs that are deregulated or mutated in neurodevelopmental and mental health diseases are fundamental to understanding the complex transcriptional processes in brain function. Crucially, lncRNAs can be exploited as a novel target for treating neurological disorders. In our review, we first summarize the recent advances in our understanding of lncRNA functions in the context of cell biology and then discussing their association with selected neuronal development and neurological disorders.
In the central nervous system, cholesterol is critical to maintain membrane plasticity, cellular function, and synaptic integrity. In recent years, much attention was focused on the role of cholesterol in brain since a breakdown of cholesterol metabolism has been associated with different diseases. Brain-derived neurotrophic factor (BDNF) was previously reported to elicit cholesterol biosynthesis and promote the accumulation of presynaptic proteins in cholesterol-rich lipid rafts, but no data are available on its ability to modulate physiological mechanisms involved in cholesterol homeostasis. Major aim of this research was to investigate whether BDNF influences cholesterol homeostasis, focusing on the effect of the neurotrophin on Apolipoprotein E (ApoE) synthesis, cholesterol efflux from astrocytes and cholesterol incorporation into neurons. Our results show that BDNF significantly stimulates cholesterol efflux by astrocytes, as well as ATP binding cassette A1 (ABCA1) transporter and ApoE expression. Conversely, cholesterol uptake in neurons was downregulated by BDNF. This effect was associated with the increase of Liver X Receptor (LXR)-beta expression in neuron exposed to BDNF. The level of apoptosis markers, that is, cleaved caspase 3 and poly ADP ribose polymerase (PARP), was found increased in neurons treated with high cholesterol, but significantly lower when the cells were exposed to cholesterol in the presence of BDNF, thus suggesting a neuroprotective role of the neurotrophin, likely through its reducing effect of neuronal cholesterol uptake. Interestingly, cholesterol stimulates BDNF production by neurons. Overall, our findings evidenced a novel role of BDNF in the modulation of ApoE and cholesterol homeostasis in glial and neuronal cells.
Brain-derived neurotrophic factor (BDNF) is a neurotrophin family member that is highly expressed and widely distributed in the brain. BDNF is critical for neural survival and plasticity both during development and in adulthood, and dysfunction in its signaling may contribute to a number of neurodegenerative disorders. Deep understanding of the BDNF-activated molecular cascade may thus help to find new biomarkers and therapeutic targets. One interesting direction is related to the early phase of BDNF-dependent gene expression regulation, which is responsible for the activation of selective gene programs that lead to stable functional and structural remodeling of neurons. Immediate-early coding genes activated by BDNF are under investigation, but the involvement of the non-coding RNAs is largely unexplored, especially the long non-coding RNAs (lncRNAs). lncRNAs are emerging as key regulators that can orchestrate different aspects of nervous system development, homeostasis, and plasticity, making them attractive candidate markers and therapeutic targets for brain diseases. We used microarray technology to identify differentially expressed lncRNAs in the immediate response phase of BDNF stimulation in a neuronal cell model. Our observations on the putative functional role of lncRNAs provide clues to their involvement as master regulators of gene expression cascade triggered by BDNF.
EGR1 is a transcription factor expressed in many cell types that regulates genes involved in different biological processes including growth, proliferation, and apoptosis. Dysregulation of EGR1 expression has been associated with many pathological conditions such as tumors and brain diseases. Known molecular mechanisms underlying the control of EGR1 function include regulation of transcription, mRNA and protein stability, and post-translational modifications. Here we describe the identification of a splicing isoform for the human EGR1 gene. The newly identified splicing transcript encodes a shorter protein compared to the canonical EGR1. This isoform lacks a region belonging to the N-terminal activation domain and although it is capable of entering the nucleus, it is unable to activate transcription fully relative to the canonical isoform.
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