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neuronal death. This neuronal death associated with knockdown of
Adar2
was
rescued by expression of the edited
GluR-B (R)
transcript in neuronal cells which
ADAR2
/
mouse (Higuchi
is similar to the rescue of the
et al.
, 2000). In
addition, ectopic expression of
was shown to have a protective effect.
The authors also demonstrated that expression of ADAR2 is regulated by cyclic
AMP response element binding protein (CREB) that is decreased in CA1
pyramidal neurons following ischemic insult (Peng
ADAR2
et al.
, 2006). Taken together,
these results demonstrate that editing of
transcripts at the Q/R site by
ADAR2 is critical in neuronal cell death following ischemia. However, other
factors such as the abundance of calcium binding proteins and calcium pumps
can influence the outcome.
GluR-B
XIV. ADAR2 AS A “NEURONAL GATEKEEPER”
ALS is a progressive, degenerative disease characterized by a selective loss of motor
neurons that leads to paralysis and death, and currently there is no effective
treatment. Editing of the
transcript was investigated as motor neurons are
vulnerable to AMPA receptor-mediated neurotoxicity similar to CA1 pyramidal
neurons (reviewed in Kwak andKawahara, 2005). Editing at theQ/R position of the
GluR-B
GluR-B
transcript was analyzed in single motor neurons isolated by laser-capture
microdissection from the spinal cord of patients with ALS and controls. Editing
efficiency was 100% in control motor neurons; however, motor neurons form ALS
patients showed a range of 0-100% editing, with an average of approximately 60%
(Kawahara
,2004). The decrease in editing was specific to themotor neurons as
editing in Purkinje cells from these patients was 100%, and it was also specific to
sporadic ALS patients. However, loss of
et al.
site editing is not observed in
motor neurons from patients with familial ALS (fALS) or rat models of fALS that
contain mutations in the
GluR-B Q/R
gene, indicating despite presenting with similar
symptoms there are multiple causes for the pathogenesis of ALS (Kawahara
SOD1
,
2006). This work onALS has led to the hypothesis that GluR-B acts as a “neuronal
gatekeeper” in the same manner as the model of ischemic injury, such that de-
creased editing of the
et al.
site renders the neuron permeable to calcium
which leads to cell death (Buckingham
GluR-B Q/R
et al.
,2008).
XV. ADAR AND ALTERNATIVE SPLICING
Many mRNAs are alternatively spliced to generate multiple mature mRNAs
which can have distinct functions from one pre-mRNA (reviewed in Black,
2003). As editing occurs prior to splicing and the editing sites are often close to
splice sites, one obvious question is whether editing influences splicing and in
