Selected Grantee Publications
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- Neurological
Mechanism of STMN2 Cryptic Splice-Polyadenylation and its Correction for TDP-43 Proteinopathies
Baughn et al., Science. 2023.
Loss of the RNA-binding protein TDP-43 from the nuclei of affected neurons is a hallmark of neurodegeneration in TDP-43 proteinopathies (e.g., amyotrophic lateral sclerosis, frontotemporal dementia). Loss of functional TDP-43 is accompanied by misprocessing of the stathmin-2 (STMN2) RNA precursor. Investigators determined the elements through which TDP‑43 regulates STMN2 pre‑mRNA processing and identified steric binding antisense oligonucleotides that are capable of restoring normal STMN2 protein and RNA levels. This approach is potentially applicable for human therapy. Supported by ORIP (U42OD010921), NIA, NCI, NIGMS, and NINDS.
Chronic Immune Activation and Gut Barrier Dysfunction Is Associated with Neuroinflammation in ART-Suppressed SIV+ Rhesus Macaques
Byrnes et al., PLOS Pathogens. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10085024/
About 40% of people with HIV develop neurocognitive disorders, potentially resulting from persistent infection in the brain and neuroinflammation. Investigators characterized the central nervous system reservoir and immune environment of simian immunodeficiency virus (SIV)–infected rhesus macaques of both sexes during acute, chronic, or antiretroviral therapy (ART)–suppressed infection. They reported that neuroinflammation and blood–brain barrier dysfunction correlated with viremia and immune activation in the gut. Their findings suggest that gastrointestinal tract damage can contribute to neuroimmune activation and inflammation, even in the absence of SIV or HIV infection. This work also has implications for other neurological disorders where chronic inflammation is associated with pathogenesis. Supported by ORIP (P51OD011132, P51OD011092, U42OD011023, R24OD010445), NIAID, NCI, and NIMH.
Cannabinoids Modulate the Microbiota–Gut–Brain Axis in HIV/SIV Infection by Reducing Neuroinflammation and Dysbiosis while Concurrently Elevating Endocannabinoid and Indole-3-Propionate Levels
McDew-White et al., Journal of Neuroinflammation. 2023.
https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-023-02729-6
Chronic neuroinflammation is thought to be a significant contributor to HIV-associated neurocognitive disorders. Using rhesus macaques of both sexes, researchers investigated the effects of simian immunodeficiency virus (SIV) infection on the microbiota–gut–brain axis (MGBA), as well as the use of low-dose cannabinoids to reverse MGBA dysregulation. They reported that tetrahydrocannabinol reduced neuroinflammation and dysbiosis and increased plasma endocannabinoid, endocannabinoid-like, glycerophospholipid, and indole-3-propionate levels. This study offers a potential strategy to promote brain health in people with HIV. Supported by ORIP (P51OD011104, P51OD011103), NIAID, and NIDA.
A Class of Anti-Inflammatory Lipids Decrease with Aging in the Central Nervous System
Tan et al., Nature Chemical Biology. 2023.
https://doi.org/10.1038/s41589-022-01165-6
Impaired lipid metabolism in the brain has been implicated in neurological disorders of aging, yet analyses of lipid pathway changes with age have been lacking. The researchers examined the brain lipidome of mice of both sexes across the lifespan using untargeted lipidomics. They found that 3-sulfogalactosyl diacylglycerols (SGDGs) are structural components of myelin and decline with age in the central nervous system. The researchers discovered that SGDGs also are present in male human and rhesus macaque brains, demonstrating their evolutionary conservation in mammals. The investigators showed that SGDGs possess anti-inflammatory activity, suggesting a potential role for this lipid class in age-related neurodegenerative diseases. Supported by ORIP (P51OD011092), NIA, NCI, NIDDK, and NINDS.
PIKFYVE Inhibition Mitigates Disease in Models of Diverse Forms of ALS
Hung et al., Cell . 2023.
https://doi.org/10.1016/j.cell.2023.01.005
Investigators showed that pharmacological suppression of PIKFYVE activity reduces pathology and extends survival of animal models and patient-derived motor neurons representing diverse forms of amyotrophic lateral sclerosis (ALS). Upon PIKFYVE inhibition, exocytosis is activated to transport aggregation-prone proteins out of the cells, a process that does not require stimulating macroautophagy or the ubiquitin-proteosome system. These findings suggest therapeutic potential to manage multiple forms of ALS. Supported by ORIP (S10OD021553) and NINDS.
Chronic TREM2 Activation Exacerbates Aβ-Associated Tau Seeding and Spreading
Jain et al., Journal of Experimental Medicine. 2023.
Using a mouse model for amyloidosis in which Alzheimer’s Disease (AD)–associated tau is injected into the brain to induce amyloid β (Aβ)–dependent tau seeding/spreading, investigators found that chronic administration of an activating triggering receptor expressed on myeloid cells 2 (TREM2) antibody increases microglial activation of dystrophic neurites surrounding Aβ plaques (NP) but increases NP-tau pathology and neuritic dystrophy without altering Aβ plaque burden. These data suggest that sustained microglial activation through TREM2 that does not result in strong myeloid removal might exacerbate Aβ-induced tau pathology, which could have important clinical implications. Supported by ORIP (S10OD021629) and NIA.
TMEM161B Modulates Radial Glial Scaffolding in Neocortical Development
Wang et al., PNAS. 2023.
https://www.pnas.org/doi/10.1073/pnas.2209983120
Neocortical folding (i.e., gyrification) is a fundamental evolutionary mechanism allowing the expansion of cortical surface area and increased cognitive function. This study identifies TMEM161B in gyral spacing in humans, likely affecting radial glial cell polarity through effects on the actin cytoskeleton. Patients carrying TMEM161B mutations exhibit striking neocortical polymicrogyria and intellectual disability. TMEM161B knockout mice fail to develop midline hemispheric cleavage, whereas knock-in of patient mutations and patient-derived brain organoids show defects in apical cell polarity and radial glial scaffolding. The data implicating TMEM161B in murine holoprosencephaly may suggest shared mechanisms between the formation of the brain midline and cortical gyrification. Supported by ORIP (U54OD030187), NINDS, and NHGRI.
PGRN Deficiency Exacerbates, Whereas a Brain Penetrant PGRN Derivative Protects, GBA1 Mutation–Associated Pathologies and Diseases
Zhao et al., Proc Natl Acad Sci USA. 2023.
https://www.pnas.org/doi/10.1073/pnas.2210442120
Mutations in GBA1 are associated with Gaucher disease (GD) and are also genetic risks in developing Parkinson’s disease (PD). Investigators created a mouse model and demonstrated that progranulin (PGRN) deficiency in Gba1 mutant mice caused early onset and exacerbated GD phenotypes, leading to substantial increases in substrate accumulation and inflammation in visceral organs and the central nervous system. These in vivo and ex vivo data demonstrated that PGRN plays a crucial role in the initiation and progression. In addition, the mouse model provides a clinically relevant system for testing therapeutic approaches for GD and PD. Supported by ORIP (R21OD033660), NIAMS, and NINDS.
Two Neuronal Peptides Encoded from a Single Transcript Regulate Mitochondrial Complex III in Drosophila
Bosch et al., eLife. 2022.
https://www.doi.org/10.7554/eLife.82709
Transcripts with small open-reading frames (smORFs) are underrepresented in genome annotations. Functions of peptides encoded by smORFs are poorly understood. The investigators systematically characterized human-conserved smORF genes in Drosophila and found two peptides, Sloth1 and Sloth2, that are highly expressed in neurons. They showed that Sloth1 and Sloth2 are paralogs with high sequence similarity but are not functionally redundant. Loss of either peptide resulted in lethality, impaired mitochondrial function, and neurodegeneration. This work suggests the value of phenotypic analysis of smORFs using Drosophila as a model. Supported by ORIP (R24OD019847), NHGRI, and NIGMS.
Sociability in a Non-Captive Macaque Population Is Associated with Beneficial Gut Bacteria
Johnson et al., Frontiers in Microbiology. 2022.
https://www.doi.org/10.3389/fmicb.2022.1032495
Social connections are essential for good health and well-being in social animals, such as humans and other primates. Increasingly, evidence suggests that the gut microbiome—through the so-called “gut–brain axis”—plays a key role in physical and mental health and that bacteria can be transmitted socially (e.g., through touch). Here, the authors explore behavioral variation in non‑captive rhesus macaques of both sexes with respect to the abundance of specific bacterial genera. Their results indicate that microorganisms whose abundance varies with individual social behavior also have functional links to host immune status. Overall, these findings highlight the connections between social behavior, microbiome composition, and health in an animal population. Supported by ORIP (P40OD012217) and NIMH.