Biology subjects

Pratt, J.

Publications and source records attributed to Pratt, J..

5 recordsLinked to original sources

bioRxiv2026

A Role for Astrocyte Metabolism in Species-Specific Neuronal Development

Human neurons develop more slowly than non-human primate (NHP) neurons, a phenomenon called neoteny, but research has primarily focused on neuron-intrinsic drivers. We hoped to further elucidate any species-specific divergence in function and the astrocytes role in influencing species-specific neurodevelopment rate. In this study, we identified a delayed onset of gliogenesis in human versus NHP organoid models. Transcriptomic and 13C metabolic flux analyses of iPSC-derived astrocytes revealed distinct metabolic profiles: NHP astrocytes exhibit increased serine and glycine synthesis, whereas human astrocytes show elevated lactate secretion, suggesting a change in the metabolic role of astrocytes across primate evolution. We then assessed the impact of these different species astrocytes on neuronal development. We observed an increase in electrophysiological maturation and a change in transcriptomic neuronal development trajectory in human neurons cultured with rhesus astrocyte conditioned media as opposed to human astrocyte conditioned media. Human astrocyte secretomes were enriched for synaptogenic and axon-growth proteins, which could indicate they play a greater role in supporting structural complexity and dendritic arborization over rapid maturation when compared to NHP astrocytes. Finally, chemical inhibition of PHGDH demonstrated that these changes in neuronal differentiation are partially mediated by the different metabolic roles that astrocytes play in humans versus NHPs. Collectively, our results reveal a cell-extrinsic role for astrocyte metabolism in shaping human-specific neurodevelopmental timing and trajectories. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/737608v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@ad88f4org.highwire.dtl.DTLVardef@fa5cf5org.highwire.dtl.DTLVardef@ecf0eborg.highwire.dtl.DTLVardef@1bcf078_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2026

Nuclear tau aggregates inhibit RNA export and form by secondary seeding from cytosolic tau aggregates.

Tau aggregates contribute to multiple neurodegenerative diseases including frontotemporal dementia and Alzheimers disease (AD). In models of tauopathy and in patient tissue, tau aggregates can form in the cytoplasm, perinuclear region, and nucleus. Using a HEK293T tau biosensor system, we identified that cytoplasmic tau aggregates formed first, followed by perinuclear-ring-like tau assemblies, and then nuclear tau aggregates formed in nuclear speckles. Nuclear tau aggregates only form in cells with pre-existing cytoplasmic tau aggregates and mostly form independently of cells traversing mitosis. Finally, nuclear tau aggregates do not contain exogenous tau seeds and arise by a secondary seeding event dependent on VCP. Nuclear tau aggregates inhibit mRNA export and show a twofold increase in poly-adenylated mRNAs in the nucleus. Together, these findings indicate that nuclear tau aggregation alters RNA biogenesis and occurs by a secondary seeding event from cytoplasmic tau aggregates, which could contribute to tau pathology.

neuroscience↗

bioRxiv2025

Polyserine-tau interactions modulate tau fibrilization

Tau aggregates are the defining feature of multiple neurodegenerative diseases and contribute to the pathology of disease. However, the molecules affecting tau aggregation in cells are unclear. We previously determined that polyserine-rich domain containing proteins enrich in tau aggregates, assemble into puncta that can serve as sites of tau aggregation, and exacerbate tau aggregation in cells and mice. Herein, we show that polyserine domains are sufficient to define assemblies as sites of tau aggregation, in part, through localization of tau seeds. Purified polyserine self-assembles and directly interacts with monomeric and fibrillar tau. Moreover, polyserine-tau assemblies recruit RNA, leading to faster rates of tau fibrillization in vitro. Using polyserine variants, we found that enrichment in tau aggregates and stimulation of tau aggregation are separable functions of polyserine domains, with polyserine self-assembly stimulating tau aggregation. Together, our results show that polyserine self-assembles and directly interacts with tau to form preferred sites of tau aggregation.

biochemistry↗

bioRxiv2022

Cytosolic condensates enriched in polyserine repeats are preferred sites of tau fiber propagation

Tau aggregates are a hallmark of multiple neurodegenerative diseases and can contain RNAs and RNA binding proteins, including SRRM2 and PNN. How these resident nuclear proteins mislocalize and their influence on the prion-like propagation of tau fibers remains unknown. We demonstrate that polyserine repeats in SRRM2 and PNN are necessary and sufficient for recruitment to tau aggregates. Moreover, we demonstrate tau fibers preferentially grow in association with endogenous cytoplasmic assemblies - mitotic interchromatin granules and cytoplasmic speckles - which contain SRRM2 and PNN. Polyserine undergoes self-assembly in vitro and in cells, where polyserine-assemblies are sites of tau fiber propagation. Modulating the levels of polyserine containing proteins results in a corresponding change in tau aggregation. These findings define a specific protein motif, and cellular condensates, that promote tau fiber propagation. As cytoplasmic speckles form in iPSC neurons under inflammatory or hyperosmolar stress, they may promote tau fiber propagation in various neurodegenerative diseases.

neuroscience↗

bioRxiv2017

Serial dependence transfers between perceptual objects

Judgments of the present visual world are affected by what came before. When judgments of visual properties such as orientation are biased in the direction of preceding stimuli, this is called visual serial dependence. Visual serial dependence is thought to arise from mechanisms that support perceptual continuity: because physical properties of an object usually vary smoothly in time, perception might be accurately stabilized by smoothing the perceived features in time. However, mechanisms that support perceptual continuity should be object-specific, because the orientation of one object is more related to its own past than to the past of a distinct object. Thus, we tested the perceptual continuity explanation by comparing the magnitude of serial dependence between objects and within objects. Across three experiments, we manipulated objecthood by varying the color, the location, and both the color and the location of Gabor patches. We observed a serial dependence effect in every experiment but did not observe an effect of objecthood in any experiment. We further observed serial dependence even when the orientations of two successive stimuli were nearly orthogonal. These data are inconsistent with explanations of serial dependence based on visual continuity. We hypothesize that serial dependence arises from a combination of perceptual features and internal response variables, which interact within a common task or decisional context.

neuroscience↗