Selected Grantee Publications
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- Neurological
- P40
- Genetics
Suppressing APOE4-Induced Neural Pathologies by Targeting the VHL-HIF Axis
Jiang et al., PNAS. 2025.
https://pubmed.ncbi.nlm.nih.gov/39874294
The ε4 variant of human apolipoprotein E (APOE4) is a major genetic risk factor for Alzheimer’s disease and increases mortality and neurodegeneration. Using Caenorhabditis elegans and male APOE-expressing mice, researchers determined that the Von Hippel-Lindau 1 (VHL-1) protein is a key modulator of APOE4-induced neural pathologies. This study demonstrated protective effects of the VHL-1 protein; the loss of this protein reduced APOE4-associated neuronal and behavioral damage by stabilizing hypoxia-inducible factor 1 (HIF-1), a transcription factor that protects against cellular stress and injury. Genetic VHL-1 inhibition also mitigated cerebral vascular injury and synaptic damage in APOE4-expressing mice. These findings suggest that targeting the VHL–HIF axis in nonproliferative tissues could reduce APOE4-driven mortality and neurodegeneration. Supported by ORIP (R24OD010943, R21OD032463, P40OD010440), NHGRI, NIA, and NIGMS.
Suppression of Viral Rebound by a Rev-Dependent Lentiviral Particle in SIV-Infected Rhesus Macaques
Hetrick et al., Gene Therapy. 2025.
https://pubmed.ncbi.nlm.nih.gov/39025983/
Viral reservoirs are a current major barrier that prevents an effective cure for patients with HIV. Antiretroviral therapy (ART) effectively suppresses viral replication, but ART cessation leads to viral rebound due to the presence of viral reservoirs. Researchers conducted in vivo testing of simian immunodeficiency virus (SIV) Rev-dependent vectors in SIVmac239-infected male and female Indian rhesus macaques, 3–6 years of age, to target viral reservoirs. Treatment with the SIV Rev-dependent vector reduced viral rebound and produced neutralizing antibodies following ART cessation. These results indicate the potential to self-control plasma viremia through a neutralizing antibody-based mechanism elicited by administration of Rev-dependent vectors. This research could guide future studies focused on investigating multiple vector injections and quantifying cell-mediated immune responses. Supported by ORIP (P51OD011104, P40OD028116), NIAID, and NIMH.
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.
Genetic Diversity of 1,845 Rhesus Macaques Improves Genetic Variation Interpretation and Identifies Disease Models
Wang et al., Nature Communications. 2024.
https://www.nature.com/articles/s41467-024-49922-6
Nonhuman primates are ideal models for certain human diseases, including retinal and neurodevelopmental disorders. Using a reverse genetics approach, researchers profiled the genetic diversity of rhesus macaque populations across eight primate research centers in the United States and uncovered rhesus macaques carrying naturally occurring pathogenic mutations. They identified more than 47,000 single-nucleotide variants in 374 genes that had been previously linked with retinal and neurodevelopmental disorders in humans. These newly identified variants can be used to study human disease pathology and to test novel treatments. Supported by ORIP (P51OD011107, P51OD011106, P40OD012217, S10OD032189), NEI, NIAID, and NIMH.
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.
Evolution of the Nitric Oxide Synthase Family in Vertebrates and Novel Insights in Gill Development
Annona et al., Proceedings of the Royal Society B. 2022.
https://www.doi.org/10.1098/rspb.2022.0667
Nitric oxide (NO) plays essential roles in biological systems, including cardiovascular homeostasis, neurotransmission, and immunity. Knowledge of NO synthases (NOS) is substantial, but the origin of nos gene orthologues in fishes, with respect to tetrapods, remains largely unknown. The recent identification of nos3 in the spotted gar, considered lost in this lineage, prompted the authors to explore nos gene evolution. Here, they report that nos2 experienced several lineage-specific gene duplications and losses. Additionally, nos3 was found to be lost independently in two teleost lineages, Elopomorpha and Clupeocephala. Further, the expression of at least one nos paralogue in gills of developing shark, bichir, sturgeon, and gar, but not in gills of lamprey, suggests nos expression in the gill might have arisen in the last common ancestor of gnathostomes. These results provide a framework for further research on the role of nos genes. Supported by ORIP (P40OD019794, R01OD011116).
Innate Immunity Stimulation via CpG Oligodeoxynucleotides Ameliorates Alzheimer’s Disease Pathology in Aged Squirrel Monkeys
Patel et al., Brain: A Journal of Neurology. 2021.
https://pubmed.ncbi.nlm.nih.gov/34128045/
Alzheimer's disease is the only illness among the top 10 causes of death for which there is no disease-modifying therapy. The authors have shown in transgenic Alzheimer's disease mouse models that harnessing innate immunity via TLR9 agonist CpG oligodeoxynucleotides (ODNs) modulates age-related defects associated with immune cells and safely reduces amyloid plaques, oligomeric amyloid-β, tau pathology, and cerebral amyloid angiopathy (CAA). They used a nonhuman primate model for sporadic Alzheimer's disease pathology that develops extensive CAA-elderly squirrel monkeys. They demonstrate that long-term use of Class B CpG ODN 2006 induces a favorable degree of innate immunity stimulation. CpG ODN 2006 has been well established in numerous human trials for a variety of diseases. This evidence together with their earlier research validates the beneficial therapeutic outcomes and safety of this innovative immunomodulatory approach. Supported by ORIP (P40OD010938), NINDS, NIA, and NCI.