Non-coding RNA transcripts: sensors of neuronal stress, modulators of synaptic plasticity, and agents of change in the onset of Alzheimer's disease

Abstract

Non-protein-coding RNAs (ncRNAs) play critical roles on many levels of cellular information processing and pervasive expression of ncRNAs in the nervous system could help explain brain complexity. NcRNAs are enriched in the central nervous system and are associated with specific neuroanatomical regions. Additionally, several recent publications have revealed an important role for deregulation of ncRNAs in various human neuropathologies, such as Alzheimer's disease, Parkinson's disease and Fragile X mental retardation. Herein, we summarize reports on functional ncRNA molecules involved in cellular stress response, particularly related to Alzheimer's disease. We conclude that ncRNAs have a prominent role in maintaining precise physiological levels of gene products directly implicated in Alzheimer's disease pathology.

Figure-1. Synaptic protein translation scaffolds contain heterogeneous and multiplexed information content; role of BC200 ncRNA

BC1 and BC200 ncRNAs, which suggested as local translational regulators, are selectively localized in somatodendritic domains of neurons. Originally discovered in 1991, by Tiedge and coworkers , BC1 and BC200 RNAs occupy a strategic position within the molecular machineries of synaptic plasticity. These RNAs regulate protein translation in the synaptic region through three proposed mechanisms of action. In the first mechanism, the analog information content of the RNA allows it to bind to Fragile X mental retardation protein (FMRP), while its digital information allows it to base pair with certain FMRP target mRNAs, achieving translational inhibition. In the second proposed mechanism the RNAs bind to Poly “A” binding protein (PABP) to inhibit translation initiation. In the third mechanism, BC1 binds to eif4a, a prototypical member of the Dead box RNA helicase family of proteins. Eif4a comprises two globular domains, the ATPase domain, and the helicase domain, and is required for translation of a certain subset of mRNAs that harbor significant secondary structure in their 5′ UTRs. Tiedge and colleagues have shown that BC1 disrupts a mechanical coupling between these two domains, thereby depriving the helicase domain of the free energy of ATP cleavage.

Figure-2. Elevated antisense RNA up-regulates β-secretase-1 in Alzheimer's disease

BACE1-AS is a non-protein-coding antisense RNA that regulates β-secretase-1 (BACE1). BACE1, a β-site amyloid precursor protein (APP)-cleaving enzyme, has been implicated in the pathogenesis of Alzheimer disease. BACE1 is involved in the production of the amyloid β (Aβ) peptides that form plaques in the brains of individuals with Alzheimer disease. (a) BACE1-AS is enriched in the nucleus in the physiologic conditions, when neurons producing basal levels of BACE1 mRNA and protein. (b) Exposure of the neuronal cells to various cell stressors, such as reactive oxygen species, chronic hypoxia and toxic metabolites, may cause cytosolic translocation of BACE1-AS transcripts. BACE1-AS can possibly form a duplex RNA with the BACE1 mRNA, leading to stabilization of this transcript and up-regulation of BACE1 protein. BACE1 protein up-regulation, in turn can produce more Aβ peptides and drive the generation of amyloid plaques. (c) Amyloid peptides and plaques are known cellular stressors and could provoke more stress to neuronal cells and lead to over-expression and release of BACE1-AS. This later event possibly drives a feed-forward mechanism resulting in neuronal cells loss. The expression of BACE1-AS is elevated in Alzheimer's disease and induces feed-forward regulation of BACE1 . It has also been shown that BACE1-AS induces production of Aβ peptides, which leads to increased expression of BACE1, which in turn further amplifies Aβ production . Subsequently, increasing Aβ levels can further boost that BACE1-AS expression, thereby accelerating the onset of Alzheimer's disease. We suggest that therapeutic targeting of BACE1-AS could mediate the transition between the essential physiological functions of BACE1 and its pathological malfunction in early Alzheimer's disease .