Abstract:
The eukaryotic initiation factor 2 (eIF2) is a protein complex which is part of the
cellular translation machinery. eIF2 comprises three subunits (α, β, γ), the γ
subunit being the one which contains a GTP-binding domain and binding sites for
the other two subunits α and β to interact. eIF2 acts in the initial part of the protein
synthesis, forming a complex with GTP and Met-tRNAMeti. This ternary complex
associates itself with the 40S subunit of the ribosome and, in a cap-dependent
manner, scans the mRNA with the help of other factors. The recognition of the
first AUG codon leads to the final assembly of the ribosome and the translation of
the protein. Due to eIF2 importance, mutations in highly conserved regions of
their genes might be lethal; however, a EIF2S3 mutation was recently found to be
responsible for intellectual disability in male patients. In those patients, signs of
problems in nervous system development are accompanied by a broad spectrum
of other symptoms such as obesity, microgenitalism and ataxia gait, a syndrome
known as MEHMO. This finding has motivated the present study in investigating
why function disruption in a central player of protein translation mainly impacts on
nervous system development. Patient-derived iPS cells were generated, and
served as the model to learn more about eIF2, its impact on the cell proteome
and its function in early neuronal development. The global translation profile from
the iPSCs was obtained by SILAC-based LC-MSMS analysis, and the expression
of candidate genes was assessed in a high-throughput manner at different time
points of neuronal differentiation. A specific increase in APOE and CRABP1
(retinoic acid related proteins) translation and transcription was observed in
patient cells, whereas CBS and TKT protein levels were decreased. Interestingly,
other genes correlated to translation regulatory mechanisms were also
differentially expressed. All this data indicates an imbalance of survival/apoptotic
pathways activation due to translational impairment. Although the present results
need further confirmation, this alteration on translation rates (iPSCs) suggests a
very early embryonic development effect of the mutation. The findings on altered
candidate proteins/mRNAs might open new avenues for future research. This
hopefully will contribute to the understanding of both, the eIF2S3 roles so far not
described and the exact functional consequences of the mutation.
iPSCs
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