Dr. Sara Young-Baird, Pharmaceutical Suppression of a Cellular Model of MEHMO Syndrome

*clock ticking* protein synthesis is a key determinant
of appropriate gene expression and as such is a highly regulated process
misregulation of protein synthesis has been implicated in the etiology of
several human disorders however the causal links between misregulated
protein synthesis and human disease remain poorly understood
to better understand how Misregulated protein synthesis contributes to disease
I’m focusing on a severe x-linked intellectual disability disorder termed
MEHMO syndrome that’s caused by mutations in Eif2 gamma a core component of
the protein synthesis machinery MEHMO patients display with several
morphological features including microcephaly a thin corpus callosum and
asymmetry of the lateral ventricles Eif2 gamma is a part of the Eif2 – gtp
initiator methionine tRNA ternary complex that both binds the initiator methionine
tRNA to the ribosome and facilitates selection of the translation start site
we found that mutations in Eif 2 gamma result in a decrease in Eif2 ternary
complex levels decreased Eif2 TC would be expected to result in a reduced
delivery of initiator methionine trna to the ribosome and accordingly we see a
decrease in both global protein synthesis and cell proliferation and
MEHMO patient induced pluripotent stem cells or iPSC’s as compared to cells
expressing wild-type Eif2 gamma mutation Eif2 gamma would also be expected to
affect gene specific protein synthesis through selection of the translation
start site and we see an increase in gene specific expression of ATF4 of
course we also wanted to ask if we could rescue the cellular phenotypes of MEHMO
syndrome using drugs that target translation initiation and to that end
we turn to the small molecule ISRIB that has previously been shown to
increase Eif2 ternary complex By treating MEHMO patient IPSC’s with ISRIB we see a
rescue of both global protein synthesis and cell proliferation ISRIB treatment is
also sufficient to reduce ATF4 expression to near wild-type levels
based off these results we think that ISRIB is a strong candidate as a potential
therapeutic for MEHMO patients and I’ll be testing this idea further with
analyses of neurons derived from the MEHMO patient IPSC’s with the ultimate
goal of understanding how misregulation of protein synthesis
contributes to the neurological phenotypes of MEHMO syndrome

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