Biology subjects

Ruck, C.

Publications and source records attributed to Ruck, C..

4 recordsLinked to original sources

bioRxiv2026

Dog-human gene network colocalization links synaptic signalling and ubiquitination to compulsive disorders

Obsessive-compulsive disorder (OCD) is highly polygenic, and the largest genome-wide association study (GWAS), with 53,660 cases and 2,044,417 controls, identified only 30 loci, a small fraction of loci estimated to explain its heritability - too few to resolve biological pathways. Pet dogs develop a compulsive disorder (dogCD) similar to OCD. In a GWAS of dogCD with 2,584 dogs from the community science project Darwin's Ark, each dog locus explains at least 40-fold more phenotypic variance than each human OCD locus, giving power equivalent to the human GWAS with 80-fold fewer individuals. Combining the two GWAS identifies a 165-gene network undetectable in humans at current sample sizes. This network is enriched for genes expressed in neurons, particularly in the amygdala and cortex, and comprises four biological processes: excitatory-inhibitory synaptic transmission, axon guidance and neuron recognition, protein ubiquitination, and adenylyl cyclase-activating G-protein-coupled receptor signaling. Like most complex human traits, dogCD risk is likely driven by regulatory variation: fine-mapped dogCD SNPs are non-coding, and dogCD loci are enriched in candidate cis-regulatory elements (cCREs) in a new dog epigenomic atlas spanning eight brain regions. The cross-species network implicates an inherited risk architecture largely outside current OCD pharmacotherapy, and establishes pet dogs as a model for gene network discovery, particularly for conditions underpowered in human studies.

genetics↗

bioRxiv2026

In Vivo 4D Oxy-Wavelet MRI as a Non-Invasive Biomarker of Brain Mitochondrial Function across the Lifespan

Mitochondria are essential for cellular energy production and are particularly critical for brain development and function. Neurons rely predominantly on oxidative phosphorylation for energy production, rendering the brain highly vulnerable to mitochondrial dysfunction. Consequently, impaired mitochondrial function contributes to a broad spectrum of neurological and systemic disorders, making mitochondria attractive therapeutic targets. Despite this importance, there is currently no non-invasive, spatially resolved method to assess mitochondrial function in the intact living brain. Here, we establish a non-invasive functional MRI approach--4D Oxy-wavelet MRI--to probe in vivo mitochondrial electron transport chain (ETC) function in a spatially specific manner across the lifespan, from fetal to adult brains. This method employs a low-rank k-t sub-Nyquist acquisition strategy to achieve simultaneous structural and functional imaging with high spatial (78 m) and temporal ([~]14 ms) resolution, enabling motion-robust imaging in multi-fetal mouse pregnancies. Mitochondrial ETC function is interrogated by measuring oxygen homeostasis responses to brief hypoxic challenges, analyzed using computational time-frequency wavelet profiling. We validate this approach in mouse models of mitochondrial respiratory chain disease and late-onset Alzheimers disease, from in utero fetuses to adults, and demonstrate reproducibility and specificity using pharmacological hyperemia and ETC complex I inhibition. We further show parallel wavelet responses in placenta and fetal brain, enabling multi-organ interrogation of the placenta-brain axis. Finally, we present first-in-human feasibility data, supporting translational potential for non-invasive assessment of mitochondrial function in living brains across the lifespan.

bioengineering↗

bioRxiv2024

Mitigation of Fetal Irradiation Injury from Mid-Gestation Total Body Radiation with Mitochondrial-Targeted GS-Nitroxide JP4-039

Victims of a radiation terrorist event will include pregnant women and unborn fetuses. Mitochondrial dysfunction and oxidative stress are key pathogenic factors of fetal irradiation injury. The goal of this preclinical study is to investigate the efficacy of mitigating fetal irradiation injury by maternal administration of the mitochondrial-targeted gramicidin S (GS)- nitroxide radiation mitigator, JP4-039. Pregnant female C57BL/6NTac mice received 3 Gy total body ionizing irradiation (TBI) at mid-gestation embryonic day 13.5 (E13.5). Using novel time- and-motion-resolved 4D in utero magnetic resonance imaging (4D-uMRI), we found TBI caused extensive injury to the fetal brain that included cerebral hemorrhage, loss of cerebral tissue, and hydrocephalus with excessive accumulation of cerebrospinal fluid (CSF). Histopathology of the fetal mouse brain showed broken cerebral vessels and elevated apoptosis. Further use of novel 4D Oxy-wavelet MRI capable of probing in vivo mitochondrial function in intact brain revealed significant reduction of mitochondrial function in the fetal brain after 3Gy TBI. This was validated by ex vivo Oroboros mitochondrial respirometry. Maternal administration JP4-039 one day after TBI (E14.5), which can pass through the placental barrier, significantly reduced fetal brain radiation injury and improved fetal brain mitochondrial respiration. This also preserved cerebral brain tissue integrity and reduced cerebral hemorrhage and cell death. As JP4-039 administration did not change litter sizes or fetus viability, together these findings indicate JP4-039 can be deployed as a safe and effective mitigator of fetal radiation injury from mid-gestational in utero ionizing radiation exposure. One Sentence SummaryMitochondrial-targeted gramicidin S (GS)-nitroxide JP4-039 is safe and effective radiation mitigator for mid-gestational fetal irradiation injury.

developmental biology↗

bioRxiv2017

Evolutionary and functional data power search for obsessive-compulsive disorder genes

Obsessive-compulsive disorder (OCD) is a severe psychiatric disorder linked to abnormalities in the cortico-striatal circuit and in glutamate signaling. We sequenced coding and regulatory elements for 608 genes implicated in OCD from humans and two animal models (mouse and dog). Using a new method, PolyStrat, which prioritizes variants disrupting evolutionarily conserved, functional regions, we found four strongly associated genes when comparing 592 cases to 560 controls. These results were validated in a second, larger cohort. NRXN1 and HTR2A are enriched for coding variants altering postsynaptic protein-binding domains, while CTTNBP2 (synapse maintenance) and REEP3 (vesicle trafficking) are enriched for regulatory variants. The rare coding variant burden in NRXN1 achieves genomewide significance (p=6.37x10-11) when we include public data for 33,370 controls. Of 17 regulatory variants identified in CTTNBP2 and REEP3, we show that at least six alter transcription factor-DNA binding in human neuroblastoma cells. Our findings suggest synaptic adhesion as a key function in compulsive behaviors across three species, and demonstrate how combining targeted sequencing with functional annotations can identify potentially causative variants in both coding and noncoding regions, even when genomic data is limited.

genomics↗