Figure 2

ASD mutation-induced redox-sensitive protein signatures compromise core synaptic functions in autism. (A) The ribosome recruits mRNAs, encoding proteins for specific pathways (black, green, blue mRNAs). Subsets of mRNAs are under the control of the translational regulator RPL10 (orange), which itself is controlled by upstream regulators (grey). This forms a protein signature characteristic for example for mRNA and protein metabolism (black), redox-metabolism (green) and energy metabolism (blue). (B) In the presence of (mis)functional RPL10 variants (for example, RPL10[H213Q]) or other ASD variants (red crosses) regulating RPL10 the protein signatures are selectively shifted (red rectangles) resulting in alterations (change in number of the framed protein spots) of pathway-specific redox-sensitive proteins as observed here. The altered protein signature thus indicates a response to oxidative stress elicited by the ASD mutation(s). (C) In peripheral tissues, for example, a lymphoblast, deficiencies in RPL10 or upstream regulators thereof alter the redox-sensitive signature in a way which in the presence of moderate ROS (reactive oxygen species) production (small red bolt) is still able to balance cellular stress response. In particular, altered expression of the glycolytic enzyme GAPDH (blue) may be employed for redox buffering by rerouting glycolysis into the PPP (pentose phosphate pathway). This will increase reductive power to balance oxidative power caused by ROS. (D) Under conditions of high oxygen metabolism (large red bolt) as present in neural cells, redox buffering will still support basal synaptic functions, but may no longer be able to prevent oxidative damage of lipids and proteins required for cellular fine-tuning (undulations) of synaptic functions and plasticity (purple, double headed arrow). We hypothesize that the effect of different ASD-mutation induced protein signatures would drive individual autistic phenotypes with differential failure to secure correct executing of synaptic plasticity. Question marks indicate unknown individual steps. ASD, autism spectrum disorders.