Biology subjects

Zaltsman, Y.

Publications and source records attributed to Zaltsman, Y..

5 recordsLinked to original sources

bioRxiv2023

Autism genes converge on microtubule biology and RNA-binding proteins during excitatory neurogenesis

Recent studies have identified over one hundred high-confidence (hc) autism spectrum disorder (ASD) genes. Systems biological and functional analyses on smaller subsets of these genes have consistently implicated excitatory neurogenesis. However, the extent to which the broader set of hcASD genes are involved in this process has not been explored systematically nor have the biological pathways underlying this convergence been identified. Here, we leveraged CROP-Seq to repress 87 hcASD genes in a human in vitro model of cortical neurogenesis. We identified 17 hcASD genes whose repression significantly alters developmental trajectory and results in a common cellular state characterized by disruptions in proliferation, differentiation, cell cycle, microtubule biology, and RNA-binding proteins (RBPs). We also characterized over 3,000 differentially expressed genes, 286 of which had expression profiles correlated with changes in developmental trajectory. Overall, we uncovered transcriptional disruptions downstream of hcASD gene perturbations, correlated these disruptions with distinct differentiation phenotypes, and reinforced neurogenesis, microtubule biology, and RBPs as convergent points of disruption in ASD.

systems biology↗

bioRxiv2023

High-energy demand and nutrient exhaustion in MTCH2 knockout cells

Mitochondrial carrier homolog 2 (MTCH2) is a regulator of apoptosis, mitochondrial dynamics, and metabolism. Loss of MTCH2 results in mitochondrial fragmentation, an increase in whole-body energy utilization, and protection from diet-induced obesity. We now show using temporal metabolomics that MTCH2 deletion results in a high ATP demand, an oxidized environment, a high lipid/amino acid/carbohydrate metabolism, and in the decrease of many metabolites. Lipidomics analyses show a strategic adaptive decrease in membrane lipids and an increase in storage lipids in MTCH2 knockout cells. Importantly, all the metabolic changes in the MTCH2 knockout cells were rescued by MTCH2 re-expression. Interestingly, this imbalance in energy metabolism and reductive potential triggered by MTCH2-deletion inhibits adipocyte differentiation, an energy consuming reductive biosynthetic process. In summary, loss of MTCH2 results in an increase in energy demand that triggers a catabolic and oxidizing environment, which fails to fuel the anabolic processes during adipocyte differentiation.

cell biology↗

bioRxiv2023

A foundational atlas of autism protein interactions reveals molecular convergence

Translating high-confidence (hc) autism spectrum disorder (ASD) genes into viable treatment targets remains elusive. We constructed a foundational protein-protein interaction (PPI) network in HEK293T cells involving 100 hcASD risk genes, revealing over 1,800 PPIs (87% novel). Interactors, expressed in the human brain and enriched for ASD but not schizophrenia genetic risk, converged on protein complexes involved in neurogenesis, tubulin biology, transcriptional regulation, and chromatin modification. A PPI map of 54 patient-derived missense variants identified differential physical interactions, and we leveraged AlphaFold-Multimer predictions to prioritize direct PPIs and specific variants for interrogation in Xenopus tropicalis and human forebrain organoids. A mutation in the transcription factor FOXP1 led to reconfiguration of DNA binding sites and altered development of deep cortical layer neurons in forebrain organoids. This work offers new insights into molecular mechanisms underlying ASD and describes a powerful platform to develop and test therapeutic strategies for many genetically-defined conditions.

systems biology↗

bioRxiv2022

Pleiotropy of autism-associated chromatin regulators

Gene ontology analyses of high confidence autism spectrum disorder (hcASD) risk genes have historically highlighted chromatin regulation and synaptic function as major contributors to pathobiology. Our recent functional work in vivo has additionally implicated microtubule biology and identified disrupted cellular proliferation as a convergent ASD phenotype. As many chromatin regulators, including ASD risk genes ADNP and CHD3, are known to directly regulate both tubulins and histones, we studied the five chromatin regulators most strongly associated with ASD (ADNP, CHD8, CHD2, POGZ, and SUV420H1/KMT5B) specifically with respect to microtubule biology. We observe that all five localize to microtubules of the mitotic spindle in vitro and in vivo. Further in-depth investigation of CHD2 provides evidence that patient-derived mutations lead to a range of microtubule-related phenotypes, including disrupted localization of the protein at the mitotic spindle, spindle defects, cell cycle stalling, DNA damage, and cell death. Lastly, we observe that ASD genetic risk is significantly enriched among microtubule-associated proteins, suggesting broader relevance. Together, these results provide further evidence that the role of tubulin biology and cellular proliferation in ASD warrant further investigation and highlight the pitfalls of relying solely on annotated gene functions in the search for pathological mechanisms.

developmental biology↗

bioRxiv2022

MTCH2 cooperates with MFN2 and lysophosphatidic acid synthesis to sustain mitochondrial fusion

Mitochondrial dynamics is critical to sustain normal mitochondrial function and is linked to the response of cells to stressful conditions. Fusion of the outer mitochondrial membrane (OMM) is regulated by mitofusin 1 (MFN1) and 2 (MFN2), yet the differential contribution of each of these proteins to this process is less understood. Mitochondrial carrier homolog 2 (MTCH2) was shown to compensate for MFN2s loss, however its exact function in mitochondrial fusion remains poorly understood. Here we determined the mitochondrial fusion-interplay between MFN1, MFN2 and MTCH2 and demonstrate that MFN2 and MTCH2 play separate, but redundant, roles required for mitochondrial fusion. Loss of either MFN2 or MTCH2 elicits mitochondrial fragmentation that retains mitochondrial plasticity, while loss of both proteins completely impairs mitochondrial fusion. We also show that expression of an MFN2 mutant targeted to the endoplasmic reticulum (ER) is sufficient to restore mitochondrial elongation in MTCH2 KO cells and that this restoration depends on the synthesis of the pro-mitochondrial fusion lipid lysophosphatidic acid (LPA). Moreover, silencing of MFN2 or inhibition of de novo LPA synthesis, revealed the requirement of MTCH2 to sustain mitochondrial plasticity in response to stress. Thus, we unmask two cooperative mechanisms that sustain mitochondrial fusion: one in the OMM, dependent on MTCH2 and MFN1, and independent of MFN2; and a second mechanism in the ER that relies on MFN2 and LPA synthesis.

cell biology↗