Abstract
Disrupted in schizophrenia 1 (DISC1) is a multi-functional scaffolding protein that has been associated with neuropsychiatric disease. The role of DISC1 is to assemble protein complexes that promote neural development and signaling, hence tight control of the concentration of cellular DISC1 in neurons is vital to brain function. Using structural and biochemical techniques, we show for we believe the first time that not only is DISC1 turnover elicited by the ubiquitin proteasome system (UPS) but that it is orchestrated by the F-Box protein, FBXW7. We present the structure of FBXW7 bound to the DISC1 phosphodegron motif and exploit this information to prove that disruption of the FBXW7-DISC1 complex results in a stabilization of DISC1. This action can counteract DISC1 deficiencies observed in neural progenitor cells derived from induced pluripotent stem cells from schizophrenia patients with a DISC1 frameshift mutation. Thus manipulation of DISC1 levels via the UPS may provide a novel method to explore DISC1 function.
Highlights
Disrupted in Schizophrenia 1 (DISC1) is a susceptibility gene for a range of psychiatric disorders and was identified in a Scottish family with a high frequency of mental illness.[1]
Insights into the molecular mechanisms modulated by DISC1 only began to emerge following elucidation of the biology of DISC1-interacting proteins and protein complexes assembled by DISC1.4 As certain neuronal signaling complexes depend on DISC1 to assemble them with correct stoichiometry, it is clear that DISC1 levels must be maintained at the appropriate concentration in multiple cellular locations simultaneously
That ubiquitination was still evident in a K372R mutant, albeit occurring at a significantly lower level when compared with wildtype (Supplementary Figure 2), suggests that there may be additional ubiquitination site(s) on DISC1
Summary
Disrupted in Schizophrenia 1 (DISC1) is a susceptibility gene for a range of psychiatric disorders and was identified in a Scottish family with a high frequency of mental illness.[1]. Protein degradation by the proteosome and lysosome is a dynamic process that is crucial for neurodevelopment, synaptic plasticity and neuronal self-renewal.[5] the balance between protein synthesis and degradation in neurons is regarded as a control point for regulation of processes that underpin learning and memory.[5] Recent evidence suggests that the half-life of specific neuronal proteins can be profoundly influenced by synaptic activity, where the stoichiometry of such proteins is uniquely tailored in a manner that promotes memory formation Crucial to this process is the compartmentalization of protein turnover at the synapse, which maintains optimal levels of the evolutionarily conserved macromolecular signaling complexes that are required for neural development and synaptic transmission.[6] Interestingly, DISC1 protein levels are decreased in subjects carrying the t(1;11) DISC1 translocation,[7] a DISC1 frameshift mutation[8,9] and in the lymphocytes of a small cohort of patients diagnosed with schizophrenia.[10] DISC1 transcripts are decreased in patients with bipolar disorder.[11] In contrast, DISC1 levels appear unchanged in the hippocampus and dorsolateral prefrontal cortex of postmortem human brain samples extracted from patients with schizophrenia.[12] In addition, one study has demonstrated that DISC1 transcript levels decrease in cells collected from schizophrenic patients treated for acute psychosis, suggesting that antipsychotics might potentially regulate the levels of DISC1 in the cell.[13] These observations point to a key role for DISC1 in the development of a normally functioning brain. Nothing is known about the molecular mechanisms that fine tune DISC1 levels in neurons
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