Biology subjects

Bock, J.

Publications and source records attributed to Bock, J..

6 recordsLinked to original sources

bioRxiv2026

Anhedonia buffers the effects of early-life unpredictability on threat-reward decision-making.

Anhedonia - the diminished capacity to experience or anticipate pleasure - is among the most common consequences of early-life unpredictability, yet how these co-occurring conditions jointly shape real-world decision-making remains unknown. Here, we use a sequential foraging-under-threat task to probe motivational conflict decisions in 357 individuals varying in early-life unpredictability and anhedonia symptoms. We find that unpredictability and anhedonia exert opposing influences on choice: unpredictability shifts behavior away from the survival-optimal policy in a sex-dependent manner, while anhedonia promotes adherence to it, partly through heightened sensitivity to unexpected threatening outcomes. A mediation analysis reveals that anhedonia partially buffers the deleterious effects of unpredictability on decision quality. These results demonstrate that co-occurring conditions can mask one anothers behavioral signatures and suggest that the heterogeneous expression of transdiagnostic constructs like anhedonia may reflect context-dependent adaptations to distinct underlying etiologies.

neuroscience↗

bioRxiv2026

Longitudinal Alterations in Sleep EEG Biomarkers of Memory Consolidation in Middle-Aged and Older Adults

The precise coordination of slow oscillations (SO) and sleep spindles during non-rapid eye movement (NREM) sleep supports memory consolidation and may serve as a sensitive marker of cognitive aging. However, longitudinal changes in their oscillatory dynamics in midlife and older age remain poorly understood. Using polysomnography with high-density EEG at two timepoints over [~]2.5 years, we examined changes in local NREM slow wave (SW), sleep spindle (occurring in the 11-16 Hz sigma range), and SO-sigma coupling strength in cognitively unimpaired middle-aged to older adults at risk for Alzheimers disease. Fronto-central SO-sigma power coupling strength significantly declined over time, independent of changes in multiple measures of SW and sleep spindle expression. Local declines in multiple sleep spindle measures were also observed. Greater baseline levels of cerebrospinal fluid (CSF) neurogranin, a postsynaptic protein abundantly expressed in the dendritic spines of the hippocampus and cerebral cortex and implicated in calcium-dependent synaptic plasticity, predicted the magnitude of longitudinal decline in SO-fast sigma coupling strength, which in turn predicted episodic memory performance changes. These findings suggest that longitudinal changes in local sleep oscillatory dynamics are related to decreased synaptic integrity and may serve as an early indicator of memory decline in older adults at risk for Alzheimers disease.

neuroscience↗

bioRxiv2024

Redirecting full-length FLT1 expression towards its soluble isoform promotes postischemic angiogenesis

Vascular endothelial growth factors and their tyrosine kinase receptors are key mediators of vasculogenesis and angiogenesis with FLT1 (VEGFR1) serving as a decoy receptor. A truncated mRNA transcript encoding soluble (s) FLT1 can be generated by premature cleavage and polyadenylation (APA). Although a shortening of transcripts is described in pathological settings, including heart diseases, the functional in vivo impact of FLT1 gene isoform generation and relevance for angiogenesis remain unknown. Here, we show that specific splice site mutations within Flt1 inhibit telescripting and activate APA in vivo to efficiently modulate gene isoform expression, inducing a complete loss of full-length (fl) Flt1 and a switch towards sFlt1 in mice. FLT1 is a high-affinity decoy receptor of VEGF limiting vessel overgrowth. We show that sFLT1 was sufficient for developmental vasculogenesis, whereas flFLT1 controlled ischemia-driven angiogenesis. Our results demonstrate that telescripting is essential in vivo for controlling Flt1 isoform expression and angiogenesis and can be harnessed to improve reparative revascularization. Furthermore, given the widespread abundance of APA signals, our approach may serve as a blueprint for studying telescripting and generating other truncated gene isoforms in vivo.

cell biology↗

bioRxiv2024

TRIM52 is a primate-specific player in the DNA repair process under tight proteolytic control by a triad of giant E3 ligases

Tripartite motif 52 (TRIM52) exhibits strong positive selection in humans, yet is lost in many other mammals. In contrast to what one would expect for such a non-conserved factor, TRIM52 loss compromises cell fitness. We set out to determine the cellular function of TRIM52. Genetic and proteomic analyses revealed TRIM52s involvement in resolving topoisomerase 2 (TOP2)-DNA cross-links, mitigating DNA damage and preventing cell-cycle arrest. Consistent with a fitness-promoting function, TRIM52 is upregulated in various cancers, prompting us to investigate its regulatory pathways. We found TRIM52 to be targeted for ultra-rapid proteasomal degradation by the giant E3 ubiquitin ligases BIRC6, HUWE1, and UBR4/KCMF1. BIRC6 mono-ubiquitinates TRIM52, with subsequent extension by UBR4/KCMF1. These findings underscore TRIM52s pivotal role in DNA damage repair and regulation of its own abundance through multi-ligase degradation.

molecular biology↗

bioRxiv2022

Wnt signaling regulates passive cell competition in the retina by inducing differential cell adhesion

Self-assortation of progenitor cells during development is essential for establishment of distinct tissue identity. This is exemplified in the eye, where the early optic cup is divided into the neural retina (NR) in the center and the ciliary margin (CM) in the periphery. Previous studies have demonstrated that Wnt signaling is required for specification of the CM, but here we show that genetic ablation of Wnt signaling mediator {beta}-catenin in the peripheral optic cup failed to prevent the formation of the CM-derived ciliary body and iris in adult animals. Mosaic analysis revealed that this was only partially due to loss of adherens junctions among {beta}-catenin deficient cells, which were preferentially excluded from the CM. Even in {beta}-catenin mutant cells that can maintain adherens junctions, their inability to mediate Wnt signaling resulted in a change from P-cadherin to N-cadherin expression. We showed that this cadherin switch was sufficient to segregate otherwise identical cells into separate clusters. As a result, the ciliary body and iris were still formed after inactivation of Wnt signaling in the peripheral retina. These results showed that the dual functions of {beta}-catenin in adherens junction and Wnt signaling are required for the passive cell competition to constitute retinal compartments.

developmental biology↗

bioRxiv2019

Intramembrane protease RHBDL4 interacts with erlin complex to target unstable soluble proteins for degradation

Protein degradation is fundamentally important to ensure cell homeostasis. In the endoplasmic reticulum (ER), the ER-associated degradation (ERAD) pathway targets incorrectly folded and unassembled proteins into the cytoplasm for turnover by the proteasome. In contrast, lysosomal degradation serves as a failsafe mechanism for removing proteins that resist ERAD by forming aggregates. Previously, we showed that the ER- resident rhomboid protease RHBDL4, together with p97, mediates membrane protein degradation. However, whether RHBDL4 acts in concert with additional ERAD components is unclear, and its full substrate spectrum remains to be defined. Here, we show that besides membrane proteins, RHBDL4 cleaves aggregation-prone luminal ERAD substrates. Because RHBDL4 with mutations in the rhomboid domain leads to stabilization of substrates at the cytoplasmic side, we hypothesize that analogue to the homologue ERAD factor derlin, RHBDL4 is directly involved in substrate retrotranslocation. RHBDL4s interaction with the erlin ERAD complex and reciprocal interaction of rhomboid substrates with erlins suggest that RHBDL4 and erlins form a complex that clips substrates and thereby rescues aggregation-prone peptides in the ER lumen from terminal aggregation.

cell biology↗