Biology subjects

Mullally, C. D.

Publications and source records attributed to Mullally, C. D..

4 recordsLinked to original sources

bioRxiv2026

Full-length structure of the anti-viral and pro-tumor DNA deaminase APOBEC3B

Human APOBEC3B (A3B) restricts virus infections by catalyzing the deamination of cytosines to uracils in single-stranded DNA. A3B also contributes to mutagenesis and genome instability in cancer cells, driving tumor evolution and detrimental outcomes including therapy resistance and metastasis. A3B comprises tandem globular deaminase domains, with a multifunctional amino-terminal domain (NTD) and a catalytically active carboxy-terminal domain (CTD). Although individual domain structures have been studied, the structure of full-length A3B has remained elusive. Here, we report the cryoEM structure of wildtype A3B in complex with the natural antagonist BORF2 (the large subunit of the Epstein-Barr virus ribonucleotide reductase). The two domains of A3B bridge a novel BORF2 dimer interface, showing a unique domain positioning that distinguishes A3B from the related dual-domain retrovirus restriction factor APOBEC3G (A3G). Mutational analyses suggest that the unique NTD-CTD interaction regulates A3B deaminase activity. The BORF2 dimerization interface is stabilized by primary interactions with A3B-CTD and secondary contacts with A3B-NTD, as well as by A3B CTD-CTD dimerization. This matrix of interactions supports a molecular mechanism for A3B neutralization in which BORF2 binding leads to deaminase sequestration in large aggregates. The full-length wildtype A3B structure also provides a platform for future anti-viral and anti-cancer drug development efforts.

biochemistry↗

bioRxiv2024

Long somatic DNA-repeat expansion drives neurodegeneration in Huntington disease

Huntington Disease (HD) is a fatal genetic disease in which most striatal projection neurons (SPNs) degenerate. The central biological question about HD pathogenesis has been how the disease-causing DNA repeat expansion (CAGn) in the huntingtin (HTT) gene leads to neurodegeneration after decades of apparent latency. Inherited HTT alleles with a longer CAG repeat hasten disease onset; the length of this repeat also changes over time, generating somatic mosaicism, and genes that regulate DNA-repeat stability can influence HD age-at-onset. To understand the relationship between a cells CAG-repeat length and its biological state, we developed a single-cell method for measuring CAG-repeat length together with genome-wide RNA expression. We found that the HTT CAG repeat expands from 40-45 CAGs to 100-500+ CAGs in HD-vulnerable SPNs but not in other striatal cell types, with these long DNA-repeat expansions acquired at different times by individual SPNs. Surprisingly, somatic expansion from 40 to 150 CAGs had no apparent effect upon gene expression - but neurons with 150-500+ CAGs shared profound gene-expression changes. These expression changes involved hundreds of genes, escalated alongside further CAG-repeat expansion, eroded positive and then negative features of neuronal identity, and culminated in expression of senescence/apoptosis genes. Rates of striatal neuron loss across HD stages reflected the rates at which neurons entered this biologically distorted state. Our results suggest that HTT CAG repeats in striatal neurons undergo decades of biologically quiet expansion, then, as they asynchronously cross a high threshold, cause SPNs to degenerate quickly and asynchronously. We conclude that, at any moment in the course of HD, most neurons have an innocuous (but unstable) huntingtin gene, and that HD pathogenesis is a DNA process for almost all of a neurons life.

genetics↗

bioRxiv2024

Concerted neuron-astrocyte gene expression declines in aging and schizophrenia

Human brains vary across people and over time; such variation is not yet understood in cellular terms. Here we describe a striking relationship between peoples cortical neurons and cortical astrocytes. We used single-nucleus RNA-seq to analyze the prefrontal cortex of 191 human donors ages 22-97 years, including healthy individuals and persons with schizophrenia. Latent-factor analysis of these data revealed that in persons whose cortical neurons more strongly expressed genes for synaptic components, cortical astrocytes more strongly expressed distinct genes with synaptic functions and genes for synthesizing cholesterol, an astrocyte-supplied component of synaptic membranes. We call this relationship the Synaptic Neuron- and-Astrocyte Program (SNAP). In schizophrenia and aging - two conditions that involve declines in cognitive flexibility and plasticity 1,2 - cells had divested from SNAP: astrocytes, glutamatergic (excitatory) neurons, and GABAergic (inhibitory) neurons all reduced SNAP expression to corresponding degrees. The distinct astrocytic and neuronal components of SNAP both involved genes in which genetic risk factors for schizophrenia were strongly concentrated. SNAP, which varies quantitatively even among healthy persons of similar age, may underlie many aspects of normal human interindividual differences and be an important point of convergence for multiple kinds of pathophysiology.

neuroscience↗

bioRxiv2019

Innovations in Primate Interneuron Repertoire

Primates and rodents, which descended from a common ancestor more than 90 million years ago, exhibit profound differences in behavior and cognitive capacity. Modifications, specializations, and innovations to brain cell types may have occurred along each lineage. We used Drop-seq to profile RNA expression in more than 184,000 individual telencephalic interneurons from humans, macaques, marmosets, and mice. Conserved interneuron types varied significantly in abundance and RNA expression between mice and primates, but varied much more modestly among primates. In adult primates, the expression patterns of dozens of genes exhibited spatial expression gradients among neocortical interneurons, suggesting that adult neocortical interneurons are imprinted by their local cortical context. In addition, we found that an interneuron type previously associated with the mouse hippocampus--the \"ivy cell\", which has neurogliaform characteristics--has become abundant across the neocortex of humans, macaques, and marmosets. The most striking innovation was subcortical: we identified an abundant striatal interneuron type in primates that had no molecularly homologous cell population in mouse striatum, cortex, thalamus, or hippocampus. These interneurons, which expressed a unique combination of transcription factors, receptors, and neuropeptides, including the neuropeptide TAC3, constituted almost 30% of striatal interneurons in marmosets and humans. Understanding how gene and cell-type attributes changed or persisted over the evolutionary divergence of primates and rodents will guide the choice of models for human brain disorders and mutations and help to identify the cellular substrates of expanded cognition in humans and other primates.

neuroscience↗