Biology subjects

Sheehan, P. W.

Publications and source records attributed to Sheehan, P. W..

5 recordsLinked to original sources

bioRxiv2025

Reconstructed Cell-Type Specific Rhythms in Human Brain link Alzheimer's Pathology, Circadian Stress, and Ribosomal Disruption

Alzheimers disease (AD) disrupts behavioral circadian rhythms, but its effects on molecular rhythms in the human brain are poorly understood. Using single-nucleus RNA sequencing from post-mortem cortical samples, we informatically estimated the relative circadian phases of 409 persons with and without AD dementia. We then reconstructed circadian expression profiles across cell types. While core clock rhythms were preserved in AD, many cell-type specific circadian outputs were disrupted. Rhythms in ribosomal biogenesis and oxidative phosphorylation were dampened across cell types. Similar losses in ribosomal gene expression rhythms were observed in APP/PS1 mice, which showed further reductions in ribosomal protein expression and polysome-mediated translation after circadian desynchrony. Exploratory computational modeling reveals that altered translation may contribute to the increased circadian variability seen in AD patients. These findings reveal altered cell-type specific circadian output rhythms in the brains of AD affected patients, and highlight disrupted ribosomal rhythms as a feature of AD.

bioinformatics↗

bioRxiv2024

A glial circadian gene expression atlas reveals cell type and disease-specific reprogramming in response to amyloid pathology or aging.

While circadian rhythm disruption may promote neurodegenerative disease, how aging and neurodegenerative pathology impact circadian gene expression patterns in different brain cell types is unknown. Here, we used translating ribosome affinity purification methods to define the circadian translatomes of astrocytes, microglia, and bulk cerebral cortex, in healthy mouse brain and in the settings of amyloid-beta plaque pathology or aging. Our data reveal that glial circadian translatomes are highly cell type-specific and exhibit profound, context-dependent reprogramming of rhythmic transcripts in response to amyloid pathology or aging. Transcripts involved in glial activation, immunometabolism, and proteostasis, as well as nearly half of all Alzheimer Disease (AD)-associated risk genes, displayed circadian oscillations, many of which were altered by pathology. Amyloid-related differential gene expression was also dependent on time of day. Thus, circadian rhythms in gene expression are cell- and context dependent and provide important insights into glial gene regulation in health, AD, and aging.

neuroscience↗

bioRxiv2024

Kir6.2-KATP channels alter glycolytic flux to modulate cortical activity, arousal, and sleep-wake homeostasis

Metabolism plays an important role in the maintenance of vigilance states (e.g. wake, NREM, and REM). Brain lactate fluctuations are a biomarker of sleep. Increased interstitial fluid (ISF) lactate levels are necessary for arousal and wake-associated behaviors, while decreased ISF lactate is required for sleep. ATP-sensitive potassium (KATP) channels couple glucose-lactate metabolism with neuronal excitability. Therefore, we explored how deletion of neuronal KATP channel activity (Kir6.2-/- mice) affected the relationship between glycolytic flux, neuronal activity, and sleep/wake homeostasis. Kir6.2-/- mice shunt glucose towards glycolysis, reduce neurotransmitter synthesis, dampen cortical EEG activity, and decrease arousal. Kir6.2-/- mice spent more time awake at the onset of the light period due to altered ISF lactate dynamics. Together, we show that Kir6.2-KATP channels act as metabolic sensors to gate arousal by maintaining the metabolic stability of each vigilance state and providing the metabolic flexibility to transition between states. HighlightsO_LIGlycolytic flux is necessary for neurotransmitter synthesis. In its absence, neuronal activity is compromised causing changes in arousal and vigilance states despite sufficient energy availability. C_LIO_LIWith Kir6.2-KATP channel deficiency, the ability to both maintain and shift between different vigilance states is compromised due to changes in glucose utilization. C_LIO_LIKir6.2-KATP channels are metabolic sensors under circadian control that gate arousal and sleep/wake transitions. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=153 SRC="FIGDIR/small/581817v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@11640c6org.highwire.dtl.DTLVardef@1f6a88corg.highwire.dtl.DTLVardef@b38daborg.highwire.dtl.DTLVardef@1a061f_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2020

REV-ERBalpha mediates complement expression and circadian regulation of microglial synaptic phagocytosis

The circadian clock has been shown to regulate various aspects of brain health including microglial and astrocyte activation. Here we report that deletion of the master clock protein BMAL1 induces robust increases in the expression of complement genes such as C3, C4b and C1q in the hippocampus. Loss of downstream REV-ERB-mediated transcriptional repression led to increases in C4b in neurons and astrocytes as well as C3 protein in microglia and astrocytes. REV-ERB deletion induced complement C3/C4b gene expression and increased microglial phagocytosis of synapses in the CA3 region of the hippocampus. Finally, we observed diurnal variation in the degree of microglial synaptic phagocytosis in wild type mice which was abrogated by REV-ERB deletion. This work uncovers the BMAL1-REV-ERB axis as a regulator of complement expression and synaptic phagocytosis in the brain, thereby illuminating a novel mechanism of synaptic regulation by the circadian clock.

neuroscience↗

bioRxiv2018

Cell-autonomous regulation of astrocyte activation by the circadian clock protein BMAL1

Circadian clock dysfunction is a common symptom of aging and neurodegenerative diseases, though its impact on brain health is poorly understood. Astrocyte activation occurs in response to diverse insults, and plays a critical role in brain health and disease. We report that the core clock protein BMAL1 regulates astrogliosis in a synergistic manner via a cell-autonomous mechanism, and via a lesser non-cell-autonomous signal from neurons. Astrocyte-specific Bmal1 deletion induces astrocyte activation in vitro and in vivo, mediated in part by suppression of glutathione-s-transferase signaling. Functionally, loss of Bmal1 in astrocytes promotes neuronal death in vitro. Our results demonstrate that the core clock protein BMAL1 regulates astrocyte activation and function in vivo, elucidating a novel mechanism by which the circadian clock could influence many aspects of brain function and neurologic disease.

neuroscience↗