Biology subjects

Weiss, Y.

Publications and source records attributed to Weiss, Y..

5 recordsLinked to original sources

bioRxiv2026

Rapid early degradation of Cyclin A is important to maintain genomic stability

The Anaphase Promoting Complex/Cyclosome (APC/C) ubiquitin ligase controls mitosis by targeting the mitotic Cyclins for degradation. At Nuclear Envelope Breakdown the APC/C immediately targets CyclinA but the Spindle Assembly Checkpoint prevents it recognising CyclinB until all chromosomes have attached to the mitotic apparatus. The degradation of CyclinA before CyclinB is conserved in evolution but the physiological role of this is not yet clearly established. Overexpressing CyclinA or a non-degradable mutant interferes with chromosome congression and promotes microtubule instability, but the effect of delaying the degradation of endogenous CyclinA has not been determined. Here, we mutated two APC/C-recognition motifs in human CyclinA2 to slow down its degradation. We find that slower degradation of CyclinA alters microtubule dynamics and induces errors in chromosome congression and chromosome clustering at mitotic exit, leading to aneuploidy and malformed daughter cell nuclei. We identify Ki67 as the candidate to interfere with chromosome clustering since its phosphorylation and behaviour are perturbed when CyclinA is degraded more slowly. We conclude that rapid early CyclinA degradation is important for genomic stability.

cell biology↗

bioRxiv2026

Neuron-Specific WWOX Gene Therapy Produces Dose-Dependent, Durable Rescue in a Model of WWOX-Related Epileptic Encephalopathy

Biallelic loss-of-function mutations in WWOX cause a spectrum of neurodevelopmental disorders, including the severe, early-onset WOREE syndrome, frequently associated with intractable epilepsy and premature mortality, and the milder SCAR12, characterized by subtler neurological manifestations. While neuronal replacement of WWOX has emerged as a potential therapeutic strategy, the parameters required for safe, durable, and clinically translatable gene delivery remain undefined. Here, we systematically delineate the determinants of effective WWOX gene therapy by evaluating promoter selection, cellular targeting, vector configuration, dose, and developmental timing in a severe Wwox-null mouse model. Neuron-restricted expression driven by the human Synapsin I promoter uniquely enabled sustained phenotypic correction, whereas ubiquitous or oligodendrocyte-restricted expression failed to confer durable benefit. To better regulate transgene expression, we generated a vector lacking the WPRE element, enabling dose calibration within a clinically relevant range. Comparative dose-response analyses identified an optimal therapeutic dose of AAV9-hSynI-WWOX that produced robust, dose-dependent rescue of survival and growth. Moreover, the rescued mice displayed glucose, behavioral function and fertility indistinguishable from WT mice, accompanied by long-term restoration of WWOX DNA, transcript, and protein across central and peripheral neural tissues without detectable hepatic expression. Neuronal WWOX reconstitution promoted widespread myelination and attenuated neuroinflammatory responses, including astrogliosis and microglial activation to levels indistinguishable from WT. Continuous electrocorticographic monitoring uncovered early postnatal neuronal hyperexcitability in Wwox-null mice, which was effectively suppressed by therapeutic WWOX delivery. Finally, our data define an early postnatal therapeutic window in Wwox-null mice, showing that treatment initiated between postnatal days 1 and 5 supports durable rescue. Together, these findings define a rigorously optimized, neuron-targeted AAV9-WWOX gene therapy framework and establish critical design and timing principles for translational treatment of WWOX-associated developmental and epileptic encephalopathies.

neuroscience↗

bioRxiv2024

Reduced monitoring of task performance is an effective biomarker of autism

Can reduced flexibility in autistics behavior be a reliable classifier of autism? We asked this question in the context of pitch discrimination, which is performed with similar accuracy by autistic and non-autistic participants, matched for cognitive skills. We found that three reliable, uncorrelated characteristics quantified reduced behavioral flexibility. Most non-autistic participants showed a clear feedback-related negativity (FRN) in their EEG when incorrect, larger EEG responses during feedback following difficult versus easy trials, and increased perceptual bias following correct and easy trials versus difficult ones. All three measures were weaker in autistic participants. To assess reliability, we replicated all three measures in an experiment approximately a year later. These measures were not correlated within participants, indicating that several mechanisms, associated with anterior cingulate cortex, are atypical in autism. Together, these three measures provide group classification with above 80% accuracy, showing promise for their utility as a neurocognitive biomarker of autism. Significance statementA characteristic of autism is cognitive "slowness" in updating expectations in new contexts. Our study shows that this cognitive difference is related to a reduced use of feedback, linked to atypical activity in a brain area involved in error detection and behavioral adjustment. Using EEG, we found that autistic individuals have weaker feedback-related signals and do not adjust their behavior as effectively as non-autistic individuals. Together, these neurocognitive signals could serve as a biomarker for autism. This is the first time such brain responses have been measured in a perceptual task requiring continuous adjustments. Understanding these brain mechanisms can inform strategies to enhance learning and adaptability in autism, providing new insights into the neural basis of behavioral flexibility.

neuroscience↗

bioRxiv2023

Membrane protein sequence features direct post-translational insertion

The proper folding of multispanning membrane proteins (MPs) hinges on the accurate insertion of their transmembrane helices (TMs) into the membrane. Predominantly, TMs are inserted during protein translation, via a conserved mechanism centered around the Sec translocon. Our study reveals that the C-terminal TMs (cTMs) of numerous MPs across various organisms bypass this cotranslational route, necessitating an alternative posttranslational insertion strategy. We demonstrate that evolution has refined the hydrophilicity and length of these proteins C-terminal tails to optimize cTM insertion. Alterations in the C-tail sequence disrupt cTM insertion in both E. coli and human, leading to protein defects, loss of function, and genetic diseases. In E. coli, we identify YidC, a member of the widespread Oxa1 family, as the insertase facilitating cTMs insertion, with C-tail mutations disrupting the productive interaction of cTMs with YidC. Thus, MP sequences are fine-tuned for effective collaboration with the cellular biogenesis machinery, ensuring proper membrane protein folding.

biochemistry↗

bioRxiv2020

Loss of heterochromatin and retrotransposon silencing constitute an early phase in oocyte aging

Mammalian oocyte quality reduces with female age. A well-studied aspect of this deterioration is an age-associated rise in oocyte aneuploidy. We show that prior to the occurrence of significant aneuploidy (at the age of 9 months in mouse females), epigenetic changes occur and impact oocyte quality and maturation ability. At this age- we observe a reduction in heterochromatin marks in mouse oocytes. This decrease is apparent in both constitutive heterochromatin and facultative heterochromatin marks but is absent in active euchromatic marks which remain constant. A decrease of heterochromatin marks with age is also observed in human GV oocytes from IVF treatments. Heterochromatin loss with age is associated with an elevation in retrotransposon RNA transcription and processing, an elevation in retrotransposon protein expression, elevation in DNA repair proteins nuclear localization and oocyte maturation defects. Artificial inhibition of the heterochromatin machinery in young oocytes causes an elevation in retrotransposon expression and processing and oocyte maturation defects. Collectively, our work demonstrates an early stage of oocyte aging, characterized by the loss of heterochromatin associated chromatin marks and activation of retrotransposons which cause DNA damage and impair oocyte maturation. We hypothesize that this heterochromatin loss serves as an oocyte associated "epigenetic clock" and is exploited by the cell as an oocyte QC mechanism. One Sentence SummaryOocyte aging includes an early pre-aneuploidy phase when loss of repressive chromatin marks occurs as well as retrotransposon activation and egg maturation defects.

cell biology↗