Selected Grantee Publications
- Clear All
- 14 results found
- nigms
- 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.
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.
Molecular and Cellular Evolution of the Primate Dorsolateral Prefrontal Cortex
Ma et al., Science. 2022.
https://www.doi.org/10.1126/science.abo7257
The dorsolateral prefrontal cortex (dlPFC) exists only in primates, lies at the center of high-order cognition, and is a locus of pathology underlying many neuropsychiatric diseases. The investigators generated single-nucleus transcriptome data profiling more than 600,000 nuclei from the dlPFC of adult humans, chimpanzees, rhesus macaques, and common marmosets of both sexes. Postmortem human samples were obtained from tissue donors. The investigators’ analyses delineated dlPFC cell-type homology and transcriptomic conservation across species and identified species divergence at the molecular and cellular levels, as well as potential epigenomic mechanisms underlying these differences. Expression patterns of more than 900 genes associated with brain disorders revealed a variety of conserved, divergent, and group-specific patterns. The resulting data resource will help to vertically integrate marmoset and macaque models with human-focused efforts to develop treatments for neuropsychiatric conditions. Supported by ORIP (P51OD011133), NIA, NICHD, NIDA, NIGMS, NHGRI, NIMH, and NINDS.
Rbbp4 Loss Disrupts Neural Progenitor Cell Cycle Regulation Independent of Rb and Leads to Tp53 Acetylation and Apoptosis
Schultz-Rogers et al., Developmental Dynamics. 2022.
https://www.doi.org/10.1002/dvdy.467
Retinoblastoma binding protein 4 (Rbbp4) is a component of transcription regulatory complexes that control cell cycle gene expression by cooperating with the Rb tumor suppressor to block cell cycle entry. The authors used genetic analysis to examine the interactions of Rbbp4, Rb, and Tp53 in zebrafish neural progenitor cell cycle regulation and survival. Rbbp4 is upregulated across the spectrum of human embryonal and glial brain cancers, and it is essential for zebrafish neurogenesis. Rbbp4 loss leads to apoptosis and γ-H2AX in the developing brain that is suppressed by tp53 knockdown or maternal zygotic deletion. Mutant retinal neural precursors accumulate in M phase and fail to initiate G0 gene expression. Rbbp4; Rb1 double mutants show an additive effect on the number of M phase cells. The study demonstrates that Rbbp4 is necessary for neural progenitor cell cycle progression and initiation of G0, independent of Rb, and suggests that Rbbp4 is required for cell cycle exit and contributes to neural progenitor survival. Supported by ORIP (R24OD020166) and NIGMS.