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Multimodal Analysis of Dysregulated Heme Metabolism, Hypoxic Signaling, and Stress Erythropoiesis in Down Syndrome
Donovan et al., Cell Reports. 2024.
https://pubmed.ncbi.nlm.nih.gov/39120971
Down syndrome (DS), a genetic condition caused by the presence of an extra copy of chromosome 21, is characterized by intellectual and developmental disability. Infants with DS often suffer from low oxygen saturation, and DS is associated with obstructive sleep apnea. Investigators assessed the role that hypoxia plays in driving health conditions that are comorbid with DS. A multiomic analysis showed that people with DS exhibit elevated heme metabolism and activated stress erythropoiesis, which are indicators of chronic hypoxia; these results were recapitulated in a mouse model for DS. This study identified hypoxia as a possible mechanism underlying several conditions that co-occur with DS, including congenital heart defects, seizure disorders, autoimmune disorders, several leukemias, and Alzheimer's disease. Supported by ORIP (R24OD035579), NCATS, NCI, and NIAID.
Mechanical Force of Uterine Occupation Enables Large Vesicle Extrusion From Proteostressed Maternal Neurons
Wang et al., eLife. 2024.
https://pubmed.ncbi.nlm.nih.gov/39255003
This study investigates how mechanical forces from uterine occupation influence large vesicle extrusion (exopher production) from proteostressed maternal neurons in Caenorhabditis elegans. Exophers, previously found to remove damaged cellular components, are poorly understood. Researchers demonstrate that mechanical stress significantly increases exopher release from touch receptor neurons (i.e., ALMR) during peak reproductive periods, coinciding with egg production. Genetic disruptions reducing reproductive activity suppress exopher extrusion, whereas interventions promoting egg retention enhance it. These findings reveal that reproductive and mechanical factors modulate neuronal stress responses, providing insight on how systemic physiological changes affect neuronal health and proteostasis, with broader implications for reproductive-neuronal interactions. Supported by ORIP (R24OD010943, P40OD010440), NIA, and NIGMS.
Stat3 Mediates Fyn Kinase-Driven Dopaminergic Neurodegeneration and Microglia Activation
Siddiqui et al., Disease Models & Mechanisms. 2024.
https://pubmed.ncbi.nlm.nih.gov/39641161
The FYN gene is a risk locus for Alzheimer’s disease and several other neurodegenerative disorders. FYN encodes Fyn kinase, and previous studies have shown that Fyn signaling in dopaminergic neurons and microglia plays a role during neurodegeneration. This study investigated Fyn signaling using zebrafish that express a constitutively active Fyn Y531F mutant in neural cells. Activated neural Fyn signaling in the mutant animals resulted in dopaminergic neuron loss and induced inflammatory cytokine expression when compared with controls. Transcriptomic and chemical inhibition analyses revealed that Fyn-driven changes were dependent on the Stat3 and NF-κB signaling pathways, which work synergistically to activate neuronal inflammation and degeneration. This study provides insight into the mechanisms underlying neurodegeneration, identifying Stat3 as a novel effector of Fyn signaling and a potential translational target. Supported by ORIP (R24OD020166).
A New Atlas to Study Embryonic Cell Types in Xenopus
Petrova et al., Developmental Biology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38614285
Petrova et al. have designed a new single-cell atlas for developmental stages in Xenopus tropicalis that encompasses gastrulation, neurulation, and early tail bud. Compared to its predecessors, the new atlas enhances gene mapping, read counts, and gene/cell-type nomenclature. The atlas also leverages the latest X. tropicalis genome version to maintain consistency with previous cell-type annotations while rectifying prior nomenclature issues. The new resource emphasizes previously unexplored germ-cell populations in which novel transcription onset features have been uncovered. Finally, the new atlas offers interactive exploration through a user-friendly web portal and allows users to download complete data sets. Supported by ORIP (R24OD031956).
A Revamped Rat Reference Genome Improves the Discovery of Genetic Diversity in Laboratory Rats
de Jong, Cell Genomics. 2024.
https://www.cell.com/cell-genomics/fulltext/S2666-979X(24)00069-7
Rattus norvegicus has been used in many fields of study related to human disease; its genome was sequenced shortly after the genomes of Homo sapiens and Mus musculus. Investigators report extensive analyses of the improvements in mRatBN7.2, compared with the previous version. They conducted a broad analysis of a whole-genome sequencing data set of 163 samples from 120 inbred rat strains and substrains. Several additional resources have been created. This new assembly and its associated resources create a more solid platform for research on the many dimensions of physiology, behavior, and pathobiology of rats and can provide more reliable and meaningful translation of findings to human populations. Supported by ORIP (R24OD024617), NHGRI, NHLBI, and NIDA.
Cdk8/CDK19 Promotes Mitochondrial Fission Through Drp1 Phosphorylation and Can Phenotypically Suppress Pink1 Deficiency in Drosophila
Liao et al., Nature Communications. 2024.
https://www.nature.com/articles/s41467-024-47623-8
Pink1 is a mitochondrial kinase implicated in Parkinson’s disease and is conserved among humans, rodents, and flies. In this study, researchers found that Cdk8 in Drosophila (i.e., the orthologue of vertebrate CDK8 and CDK19) promotes the phosphorylation of Drp1 (i.e., a protein required for mitochondrial fission) at the same residue as Pink1. Cdk8 is expressed in both the cytoplasm and nucleus, and neuronal loss of Cdk8 reduces fly life span and causes bang sensitivity and elongated mitochondria in both muscles and neurons. Overexpression of Cdk8 suppresses elevated levels of reactive oxygen species, mitochondrial dysmorphology, and behavioral defects in flies with low levels of Pink1. These findings suggest that Cdk8 regulates Drp1-mediated mitochondrial fission in a similar manner as Pink1 and may contribute to the development of Parkinson’s disease. Supported by ORIP (R24OD022005, R24OD031447, P40OD018537, P40OD010949), NICHD, and NINDS.
Identifying Potential Dietary Treatments for Inherited Metabolic Disorders Using Drosophila Nutrigenomics
Martelli et al., Cell Reports. 2024.
https://www.sciencedirect.com/science/article/pii/S221112472400189X?via%3Dihub=
Inherited metabolic disorders are known to cause severe neurological impairment and child mortality and can sometimes respond to dietary treatment; however, a suitable paradigm for testing diets is lacking for developing effective dietary treatment. In this study, researchers found that 26 of 35 Drosophila amino acid disorder models screened for disease–diet interactions displayed diet-altered development and/or survival. Among these models, researchers showed that dietary cysteine depletion normalizes metabolic profile and rescues development, neurophysiology, behavior, and life span in a model for isolated sulfite oxidase deficiency. These findings demonstrate the value of using Drosophila in studying diet-sensitive metabolic disorders and developing potential dietary therapies. Supported by ORIP (R24OD031447) and NHGRI.
Epigenetic MLH1 Silencing Concurs With Mismatch Repair Deficiency in Sporadic, Naturally Occurring Colorectal Cancer in Rhesus Macaques
Deycmar et al., Journal of Translational Medicine. 2024.
https://pubmed.ncbi.nlm.nih.gov/38504345
Rhesus macaques serve as a useful model for colorectal cancer (CRC) in humans, but more data are needed to understand the molecular pathogenesis of these cancers. Using male and female rhesus macaques, researchers investigated mismatch repair status, microsatellite instability, genetic mutations, transcriptional differences, and epigenetic alterations associated with CRC. Their data indicate that epigenetic silencing suppresses MLH1 transcription, induces the loss of MLH1 protein, abrogates mismatch repair, and drives genomic instability in naturally occurring CRC in rhesus macaques. This work provides a uniquely informative model for human CRC. Supported by ORIP (P51OD011092, R24OD010947, R24OD021324, P40OD012217, U42OD010426, T35OD010946, T32OD010957), NCATS, and NCI.
CDK4/6 Inhibition Sensitizes Intracranial Tumors to PD-1 Blockade in Preclinical Models of Brain Metastasis
Nayyer et al., Clinical Cancer Research. 2024.
Brain metastases are associated with high morbidity and are often resistant to immune checkpoint inhibitors. In this study, investigators evaluated the efficacy of combining CDKi (abemaciclib) and anti–PD-1 therapy (“combination therapy”) in mouse models for brain metastases, elucidated how combination therapy remodeled the tumor–immune microenvironment (TIME) and T-cell receptor (TCR) repertoires, and investigated the effects of CDKi on T-cell development and maintenance in NOD-scid Il2rgnull (NSG) mice engrafted with human immune systems (“humanized mice”). Results offer a strong rationale for the clinical evaluation of combination CDKi and PD-1 blockade in patients with brain metastases. Supported by ORIP (R24OD026440), NCI, and NIAID.
GenomeMUSter Mouse Genetic Variation Service Enables Multitrait, Multipopulation Data Integration and Analysis
Ball et al., Genome Research. 2024.
https://genome.cshlp.org/content/34/1/145.long
Advances in genetics, including transcriptome-wide and phenome-wide association analysis methods, create compelling new opportunities for using fully reproducible and widely studied inbred mouse strains to characterize the polygenetic basis for individual differences in disease-related traits. Investigators developed an imputation approach and implemented data service to provide a broad and more comprehensive mouse variant resource. They evaluated the strain-specific imputation accuracy on a “held-out” test set that was not used in the imputation process. The authors present its application to multipopulation and multispecies analyses of complex trait variation in type 2 diabetes and substance use disorders and compare these results to human genetics studies. Supported by ORIP (U42OD010921, P40OD011102, R24OD035408), NCI, NIAAA, NIDA, and NIDCD.