Convergence of independent DISC1 mutations on impaired neurite growth via decreased UNC5D expression

Abstract

The identification of convergent phenotypes in different models of psychiatric illness highlights robust phenotypes that are more likely to be implicated in disease pathophysiology. Here, we utilize human iPSCs harboring distinct mutations in DISC1 that have been found in families with major mental illness. One mutation was engineered to mimic the consequences on DISC1 protein of a balanced translocation linked to mental illness in a Scottish pedigree; the other mutation was identified in an American pedigree with a high incidence of mental illness. Directed differentiation of these iPSCs using NGN2 expression shows rapid conversion to a homogenous population of mature excitatory neurons. Both DISC1 mutations result in reduced DISC1 protein expression, and show subtle effects on certain presynaptic proteins. In addition, RNA sequencing and qPCR showed decreased expression of UNC5D, DPP10, PCDHA6, and ZNF506 in neurons with both DISC1 mutations. Longitudinal analysis of neurite outgrowth revealed decreased neurite outgrowth in neurons with each DISC1 mutation, which was mimicked by UNC5D knockdown and rescued by transient upregulation of endogenous UNC5D. This study shows a narrow range of convergent phenotypes of two mutations found in families with major mental illness, and implicates dysregulated netrin signaling in DISC1 biology.

Focus on Causality in ESC/iPSC-Based Modeling of Psychiatric Disorders

“…These changes underpin impaired neurite outgrowth in an UNC5Ddependent manner in vitro. All in all, findings from this [37] and previous reports [34] strengthen the hypothesis that DISC1 mutations causally impact presynaptic function in vitro. Even though, we would like to emphasize again that their relevance to common psychiatric disorders remains controversial since no additional families carrying the mutations from the original index cases have been identified so far.…”

“…This promotes premature NPC differentiation and deletions impaired cortical layer formation. Rescue by Wnt-antagonists [37] [ 34,36] DISC1 See [34,36] Cortical glutamatergic Both mutations converge on few DEGs including UNCD5. iNS…”

“…More recently, Srikanth et al [37] reexamined both kinds of DISC1 mutations (i.e., the 4-bp frameshift in exon 12 and the heterozygous exon 8 deletion) in glutamatergic iNs. Mature neurons were derived from the respective isogenic wild-type and mutant iPSC lines.…”

LRRK2 Kinase Inhibition Rescues Deficits in Lysosome Function Due to Heterozygous GBA1 Expression in Human iPSC-Derived Neurons

“…These data might suggest a greater propensity for the spread of αSyn pathology, but future work in animal models will be best suited to fully address the implications of this altered αSyn release. Both lysosomal deficiency and αSyn accumulation can contribute to decreased neuronal maturation in primary rodent neurons and neuronal cell culture model (Ramonet et al, 2011;Koch et al, 2015;Wrasidlo et al, 2016;Prots et al, 2018;Srikanth et al, 2018). Accordingly, we observed that GBA1 heterozygous-null iNs display a decrease in neurite length, as well as number of neurite branch points.…”

The Plasma Peptides of Alzheimer’s Disease

“…Thus, the processing of DISC1 in AD patients apparently varied compared to all other diseases and controls. The function and mechanisms of DISC1 in Alzheimer dementia are not clear [44][45][46][47]82]. There may be some hints about the function of DISC1 by the examination of its domain architecture (Fig.…”