AB C D
Ribosome release. (A) Active translation by a ribosome scans mRNA to synthesize the corresponding protein. (B) This process stops if the ribosome cannot find tRNA bearing
the appropriate anticodon. (C) The ribosome release factor GTPBP2 recruits another factor, pelota, to release the stalled ribosome. The unfinished protein is presumably degraded
(perhaps by the proteasome). (D) The released ribosomal subunits can begin to synthesize a new protein.
lacking a matching, amino acid–charged
tRNA. These latter forms of translational
control can result in the degradation of the
mRNAs associated with these aberrantly
stalled ribosomes (7). Ishimura et al. show
that GTPBP2 functions as a ribosome release factor in this protective pathway (see
the second figure).
What Ishimura et al. then did is something often missing in similar studies—they
tested whether the neurodegenerative effects of the GTPBP2 mutation were the
same in the context of several different
genetic backgrounds. Surprisingly, they
found that loss of GTPBP2 only caused
neuronal death in one particular genetic
background of mice, the commonly used
C57BL/6J strain. This suggested that this
mutation was dependent on another gene
for its effect. The authors set off on an arduous search for the second gene. They found
it in a single nucleotide change in one of
the tRNAs that decodes the codon AGA (A,
adenine; G, guanine) (see the first figure),
causing a marked decrease in its amounts.
Remarkably, the authors found that expression of this particular tRNA—one of a set of
five that all decode AGA as the amino acid
arginine (“isodecoders”)—is brain specific.
Using elegant ribosome profiling experi-
ments (8), Ishimura et al. generated a brain-
wide map of where ribosomes are stalled,
revealing that the mutations may interfere
with the brain’s ability to make proteins
involved in carrying out translation itself,
The impact of the work by Ishimura et
al. can be felt on many levels. The authors
have discovered a new ribosome release
factor and by successfully identifying a
modifying gene, have revealed much more
about its function. Loss of GTPBP2 is only
acutely felt when there is an increased need
for it; this need is caused by excessive ri-
bosome stalling that results from limiting
amounts of a single tRNA. The further dis-
covery that one tRNA in a set of isodecod-
ers is expressed only in the brain raises the
intriguing possibility that additional spe-
cific roles remain to be discovered within
these gene families.
The strain specificity of the observed
neurodegeneration sounds a wake-up call.
The C57BL/6J strain is used in many labs,
and the work by Ishimura et al. uncovers
potential defects in brain protein translation in what the field considers to be “
wild-type” or normal C57BL/6J mice. If one can
extrapolate from the results of additional
loss of GTPBP2, which amplifies the effects of limiting amounts of the tRNA, then
it is possible that the wild-type mice also
have altered synthesis of proteins involved
in translation as well as in protein turnover, localization, mRNA processing, synaptic transmission, and regulation of the
Ribosome stalling in wild-type
C57BL/6J mice may also be exacerbated
under conditions where rapid or local
synthesis of proteins is required in the
brain—for example, when the strength of
synapses (points of contact between neu-
rons that facilitate communication) needs
to be altered by changing their size, shape,
and protein composition during learn-
ing. This is especially relevant in cases
where this mouse genetic background is
used to model human diseases in which a
mutation may affect those pathways. The
example of fragile X syndrome suggests
that caution is warranted in making con-
clusions about the function of the trans-
lational regulatory factor FMRP based on
results specific to its loss in only the par-
ticular genetic background of C57BL/6J
mouse. However, as Ishimura et al. dem-
onstrate, such strain specificity can also
be a goldmine for discovering informative
modifying genes. Both conclusions under-
score the need for increased awareness of
the effects of genetic background in model
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Laboratory of Molecular Neuro-Oncology, Rockefeller
University, 1230 York Avenue, Ne w York, NY 10065, USA.