ORIGINAL ARTICLE
Disease of mRNA Regulation: Relevance
for Ischemic Brain Injury
Donald J. DeGracia
1
Received: 11 October 2017 /Revised: 1 November 2017 /Accepted: 3 November 2017 / Published online: 10 November 2017
#
Springer Science+Business Media, LLC, part of Springer Nature 2017
Abstract In this mini-review we give an overview of the role
of mRNA-binding proteins and their associated messenger
ribonucleoprotein complexes (mRNPs) in several disease
states, and bring this information to bear on the pathophysiol-
ogy of brain ischemia. One conclusion reached is that mRNPs
may play a causal role in proteotoxicity instead of being mere-
ly passive targets. Ischemia therapies targeting mRNPs have
advantages over targeting single pathways, but the behavior of
mRNPs needs to be considered in the design of therapies.
Keywords ARE mRNA
.
Brain ischemia and reperfusion
.
ELAV
.
HuR
.
mRNA regulation
.
Stress granule
Introduction
Since the 1990s, the complexity of mRNA regulation has
become apparent. From its birth during transcription, to its
final degradation, mRNA molecules are encased in messenger
ribonucleoprotein complexes (mRNPs) formed by various
families of mRNA-binding proteins (RBPs) and many acces-
sory proteins. The mRNPs mediate major mRNA functions
including transcription, splicing, nucleocytoplasmic transport,
and in the cytoplasm, coordinate translation, silencing, or deg-
radation of functionally related groups of mRNAs. These sys-
tems play critical roles in intracellular stress responses, signal-
ing pathways, and immune system function. Given this wide
variety of function, aberrations of mRNPs and RBPs have
been implicated in a growing list of diseases.
The purpose of this mini-review is to present an overview
of some of the roles of mRNPs and RBPs in other disease
states and to integrate this with findings on mRNA regulation
after brain ischemia and reperfusion (I/R) injury. Studies of
stress granules and embryonic lethal abnormal visual (ELAV)
proteins are predominately discussed below because they have
been the most researched. While in-roads have been made on
the role of RBPs and mRNPs after brain I/R, because of the
complexity of the molecular systems, there is still a long way
to go to fully characterize the contribution of these systems to
I/R-induced brain cell death. This review is intended to pro-
vide a broad framework of mRNA dysregulation in disease
and thereby further stimulate study of these systems in the
post-ischemic brain, keeping an eye on how such findings
may give rise to novel therapeutic targets and strategies.
Ribonucleoprotein Complexes and mRNA-Binding
Proteins
The original mRNP is the ribosome, a major mRNA-binding
complex that mediates mRNAs translation. An important step
towards recognizing mRNPs as a distinct class of subcellular
entities was the discovery by Kosik and colleagues of neuro-
nal RNA granules that deliver inactive mRNAs and ribosomes
to dendrites in an activity-dependent fashion [1]. Shortly
thereafter, Kedersha, Anderson, and colleagues described in
detail the stress granule (SG) which they showed was a
Btriage^ structure that partitions mRNAs to various other
mRNP in the context of cellular stress [2, 3]. From these initial
observations and the widespread application of the underlying
techniques [4, 5], the identification of mRNPs and their con-
stituent RBPs has grown exponentially.
* Donald J. DeGracia
ddegraci@med.wayne.edu
1
Department of Physiology, and the Center for Molecular Medicine
and Genetics, Wayne State University, 4116 Scott Hall, 540 E.
Canfield, Detroit, MI 48201, USA
Transl. Stroke Res. (2018) 9:251–257
https://doi.org/10.1007/s12975-017-0586-7
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