Biology subjects

Assaf, M.

Publications and source records attributed to Assaf, M..

5 recordsLinked to original sources

bioRxiv2026

Tubulin autoregulation controls the biosynthesis of γ-tubulin to ensure mitotic fidelity

Microtubule organization relies on the precise control of tubulin abundance to ensure accurate cytoskeletal function and faithful cell division. While - and {beta}-tubulin levels are controlled by a well-characterized autoregulatory pathway that triggers co-translational mRNA decay in response to excess soluble tubulin, how cells regulate the abundance of the core microtubule nucleator {gamma}-tubulin has remained unclear. Here, we show that {gamma}-tubulin is regulated by the canonical tubulin autoregulatory machinery. We find that {gamma}-tubulin-encoding mRNAs are downregulated in response to elevated soluble {beta}-tubulin levels. This regulation requires TTC5 to co-translationally recognize a conserved amino-terminal MPREI motif in nascent {gamma}-tubulin proteins, and further recruit SCAPER and CCR4-NOT complex, targeting {gamma}-tubulin mRNAs for decay. Disruption of this regulatory mechanism elevates {gamma}-tubulin protein levels, increases centrosomal microtubule nucleation output, and compromises mitotic fidelity. Together, our findings establish {gamma}-tubulin as a previously unrecognized substrate of tubulin autoregulation and reveal coordinated control of tubulin biosynthesis as a key mechanism for tuning microtubule nucleation and ensuring accurate chromosome segregation.

cell biology↗

bioRxiv2022

Intrinsic Neural Timescales in Autism Spectrum Disorder and Schizophrenia. A Replication and Direct Comparison Study

Intrinsic neural timescales (INT) reflect the duration for which brain areas store information. A posterior - anterior hierarchy of increasingly longer INT has been revealed in both typically developed individuals (TD), as well as patients diagnosed with autism spectrum disorder (ASD) and schizophrenia (SZ), though INT are, overall, shorter in both patient groups. In the present study, we attempted to replicate previously reported group differences by comparing INT of TD to ASD and SZ. We replicated the previously reported result showing reduced INT in the left lateral occipital gyrus and the right post-central gyrus in SZ compared to TD. For the first time, we also directly compared the INT of the two patient groups and found that these same two areas show significantly reduced INT in SZ compared to ASD. In ASD, significant correlations were found between INT and their clinical and phenotypic characteristics. Our results point to the left lateral occipital gyrus and the right post-central gyrus as holding potential for further diagnostic refinement of SZ.

neuroscience↗

bioRxiv2022

Regulation of Liprin-α phase separation by CASK is disrupted by a mutation in its CaM kinase domain

CASK is a unique membrane associated guanylate kinase (MAGUK), due to its Ca2+/calmodulin-dependent kinase (CaMK) domain. We describe four male patients with a severe neurodevelopmental disorder with microcephaly carrying missense variants affecting the CaMK domain. One boy who carried the p.E115K variant and died at an early age showed pontocerebellar hypoplasia (PCH) in addition to microcephaly, thus exhibiting the classical MICPCH phenotype observed in individuals with CASK loss-of-function variants. All four variants selectively weaken the interaction of CASK with Liprin-2, a component of the presynaptic active zone. Liprin- proteins form spherical condensates in a process termed liquid-liquid phase separation (LLPS), which we observe here in Liprin-2 overexpressing HEK293T cells and primary cultured neurons. Condensate formation is reversed by interaction of Liprin-2 with CASK; this is associated with altered phosphorylation of Liprin-2. The p.E115K variant fails to interfere with condensate formation. As the individual carrying this variant had the severe MICPCH disorder, we suggest that regulation of Liprin-2-mediated LLPS is a new functional feature of CASK which must be maintained to prevent PCH.

genetics↗

bioRxiv2020

Effects of Weather and Season on Human Brain Volume

We present an exploratory cross-sectional analysis of the effect of season and weather on Freesurfer-derived brain volumes from a sample of 3,279 healthy individuals collected on two MRI scanners in Hartford, CT, USA over a 15 year period. Weather and seasonal effects were analyzed using a single linear regression model with age, sex, motion, scan sequence, time-of-day, month of the year, and the deviation from average barometric pressure, air temperature, and humidity, as covariates. FDR correction for multiple comparisons was applied to groups of non-overlapping ROIs. Significant negative relationships were found between the left- and right-cerebellum cortex and pressure (t = -2.25, p = 0.049; t = -2.771, p = 0.017). Significant positive relationships were found between left- and right-cerebellum cortex and white matter between the comparisons of January/June and January/September. Significant negative relationships were found between several subcortical ROIs for the summer months compared to January. An opposing effect was observed between the supra- and infra-tentorium, with opposite effect directions in winter and summer. Cohens d effect sizes from monthly comparisons were similar to those reported in recent psychiatric big-data publications, raising the possibility that seasonal changes and weather may be confounds in large cohort studies. Additionally, changes in brain volume due to natural environmental variation have not been reported before and may have implications for weather-related and seasonal ailments.

neuroscience↗

bioRxiv2019

Reconstructing an epigenetic landscape using a genetic ‘pulling’ approach

Cells use genetic switches to shift between alternate stable gene expression states, e.g., to adapt to new environments or to follow a developmental pathway. Conceptually, these stable phenotypes can be considered as attractive states on an epigenetic landscape with phenotypic changes being transitions between states. Measuring these transitions is challenging because they are both very rare in the absence of appropriate signals and very fast. As such, it has proven difficult to experimentally map the epigenetic landscapes that are widely believed to underly developmental networks. Here, we introduce a new nonequilibrium perturbation method to help reconstruct a regulatory networks epigenetic landscape. We derive the mathematical theory needed and then use the method on simulated data to reconstruct the landscapes. Our results show that with a relatively small number of perturbation experiments it is possible to recover an accurate representation of the true epigenetic landscape. We propose that our theory provides a general method by which epigenetic landscapes can be studied. Finally, our theory suggests that the total perturbation impulse required to induce a switch between metastable states is a fundamental quantity in developmental dynamics.

biophysics↗