One type of RNA editing converts adenosines to inosines (A-->I editing) in double-stranded RNA (dsRNA) substrates. A-->I RNA editing is mediated by adenosine deaminase acting on RNA (ADAR) enzymes. A-->I RNA editing of protein-coding sequences of a limited number of mammalian genes results in recoding and subsequent alterations of their functions. However, A-->I RNA editing most frequently targets repetitive RNA sequences located within introns and 5' and 3' untranslated regions (UTRs). Although the biological significance of noncoding RNA editing remains largely unknown, several possibilities, including its role in the control of endogenous short interfering RNAs (esiRNAs), have been proposed. Furthermore, recent studies have revealed that the biogenesis and functions of certain microRNAs (miRNAs) are regulated by the editing of their precursors. Here, I review the recent findings that indicate new functions for A-->I editing in the regulation of noncoding RNAs and for interactions between RNA editing and RNA interference mechanisms.

/pdf/functions-and-regulation-of-rna-editing-by-adar-deaminases-1j7eq0l7wm.pdf

Functions and Regulation of RNA Editing by ADAR Deaminases

The biochemical and biophysical properties of the extracellular matrix (ECM) dictate tissue-specific cell behaviour. The molecules that are associated with the ECM of each tissue, including collagens, proteoglycans, laminins and fibronectin, and the manner in which they are assembled determine the structure and the organization of the resultant ECM. The product is a specific ECM signature that is comprised of unique compositional and topographical features that both reflect and facilitate the functional requirements of the tissue.

/pdf/extracellular-matrix-assembly-a-multiscale-deconstruction-3ucggnbaz1.pdf

Extracellular matrix assembly: a multiscale deconstruction

Mechanisms of ischemic brain damage

Adenosine deaminases acting on RNA (ADARs) convert adenosine to inosine in double-stranded RNA. This A-to-I editing occurs not only in protein-coding regions of mRNAs, but also frequently in non-coding regions that contain inverted Alu repeats. Editing of coding sequences can result in the expression of functionally altered proteins that are not encoded in the genome, whereas the significance of Alu editing remains largely unknown. Certain microRNA (miRNA) precursors are also edited, leading to reduced expression or altered function of mature miRNAs. Conversely, recent studies indicate that ADAR1 forms a complex with Dicer to promote miRNA processing, revealing a new function of ADAR1 in the regulation of RNA interference.

/pdf/a-to-i-editing-of-coding-and-non-coding-rnas-by-adars-1r7hnvg690.pdf

A-to-I editing of coding and non-coding RNAs by ADARs

Research on matrix metalloproteinases (MMPs) and in particular on gelatinase B, alias MMP-9, has grown exponentially in the decade 2003–2012. Structural details about flexibility of MMP-9 monomers, together with glycosylation, oligomerization, heterogeneity and instability of the wildtype enzyme explain why crystallography experiments have not yet been successful for the intact enzyme. MMP-9 may be viewed as a multidomain enzyme in which the hemopexin, the O-glycosylated and the catalytic domains yield support for attachment, articulation and catalysis, respectively. The stepwise proteolytic activation of the inactive zymogen into a catalytically active form becomes gradually better understood. Priming of activation by MMP-3 may be executed by meprins that destabilize the interaction of the aminoterminus with the third fibronectin repeat. Alternatively, autocatalytic activation may occur in the presence of molecules that tightly bind to the catalytic site and that push the cystein residue in the p...

Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (MMP-9): The next decade

The extracellular matrix (ECM) occupies a notable proportion of the CNS and contributes to its normal physiology. Alterations to the ECM occur after neural injury (for example, in multiple sclerosis, spinal cord injury or Alzheimer's disease) and can have drastic consequences. Of note, injury-induced changes in chondroitin sulphate proteoglycans (CSPGs)--a family of ECM proteoglycans--can lead to the inhibition of myelin repair. Here, we highlight the pathophysiological roles of the brain's ECM, particularly those of CSPGs, after neural insults and discuss how the ECM can be targeted to promote remyelination.

Pathophysiology of the brain extracellular matrix: a new target for remyelination

ADAR2-Dependent RNA Editing of AMPA Receptor Subunit GluR2 Determines Vulnerability of Neurons in Forebrain Ischemia

Objective:

Failure of remyelination is a critical impediment to recovery in multiple sclerosis (MS). Chondroitin sulfate proteoglycans (CSPGs) have been reported to accumulate in MS lesions, and we thus examined the functional roles of CSPGs on oligodendrocyte precursor cells (OPCs), oligodendrocytes, and remyelination.



Methods:

We evaluated the expression of CSPGs in lysolecithin-injected mouse spinal cord, an animal model of demyelination and spontaneous remyelination. The functional impact of CSPGs on OPCs and remyelination was investigated using cultured adult murine and human OPCs and by treating demyelinated mice with xyloside to reduce the CSPG deposition that occurred following injury.



Results:

Early and robust upregulation of CSPGs following lysolecithin-induced demyelination was cleared during remyelination. In culture, CSPGs anchored onto the substratum reduced the adhesion of mouse and human OPCs and their subsequent morphological differentiation into process-bearing oligodendrocytes. Soluble CSPGs added to already adherent OPCs reduced the development of processes, whereas the acquisition of mature myelin proteins was unimpeded. Stripe assays of alternating CSPG and control substrata confirmed the nonpermissive nature of CSPGs for OPC adhesion and morphological differentiation. Enzymatic degradation of CSPGs with chondroitinase ABC was sufficient to overcome CSPG-dependent inhibition of human oligodendrocytes. Finally, in vivo xyloside treatment to reduce CSPG synthesis in lysolecithin-demyelinated mice increased numbers of OPCs and oligodendrocytes in lesions, and culminated in improved remyelination.



Interpretation:

These results identify CSPGs as a nonpermissive substrate for OPCs and oligodendrocytes, and as a prominent impediment to remyelination. The data suggest the requirement for the neutralization of CSPGs for repair after demyelination. ANN NEUROL 2012;72:419–432.

Chondroitin sulfate proteoglycans in demyelinated lesions impair remyelination.

MMPs in the central nervous system: where the good guys go bad.

https://www.cell.com/neuron/pdf/S0896-6273(04)00364-2.pdf

Lorraine Lau

Papers

Pathophysiology of the brain extracellular matrix: a new target for remyelination

ADAR2-Dependent RNA Editing of AMPA Receptor Subunit GluR2 Determines Vulnerability of Neurons in Forebrain Ischemia

Chondroitin sulfate proteoglycans in demyelinated lesions impair remyelination.

MMPs in the central nervous system: where the good guys go bad.

Expression of Ca2+-Permeable AMPA Receptor Channels Primes Cell Death in Transient Forebrain Ischemia