Biology subjects

Nolan, M.

Publications and source records attributed to Nolan, M..

12 recordsLinked to original sources

bioRxiv2026

Statins and genetic inhibition of the mevalonate pathway activate an ATF3-STMN2 regenerative program

Loss of neuronal regenerative capacity is a common feature of neurodegenerative disease and axonal injury, yet the transcriptional programs governing this state remain poorly defined. Stathmin-2 (STMN2), a tubulin-binding protein essential for axon maintenance and repair, is profoundly depleted following loss of nuclear TDP-43 in neurodegenerative disease. Here, we identify statins as potent inducers of STMN2 expression. Pharmacological and genetic suppression of the mevalonate pathway, and subsequent prevention of protein geranylgeranylation, restored STMN2 levels in TDP-43 deficient cells and promoted neurite growth. STMN2 induction was abrogated when using a statin analogue unable to interact with HMG-CoA reductase, and through co-administration of mevalonate or geranylgeranyl diphosphate substrates. RNA-seq revealed that statins induce a coordinated pro-regenerative transcriptional response, including activation of the AP-1 transcription factor complex gene, ATF3. Loss of ATF3 attenuated STMN2 induction in vitro, and diminished injury-induced Stmn2 upregulation in spinal motor neurons in vivo. These results demonstrate statins as modulators of ATF3 and STMN2 expression and highlight their therapeutic potential in neurodegenerative disease.

neuroscience↗

bioRxiv2026

STMN2 protein depletion via translation deficits and stress granules and its compensation in ALS

STMN2 is an abundant neurospecific protein dysregulated in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). We previously reported that cellular stress can lead to STMN2 loss due to TDP-43 nuclear condensation. Here, using human and murine neuronal cell models, multiple pharmacological tools, single-molecule in situ analysis of mRNA localisation and translation, and longitudinal analysis of neuronal fitness/survival, we establish TDP-43-independent mechanisms of STMN2 depletion linked to stress response. We find that human STMN2 protein is extremely labile under acute high-magnitude stress. Early in stress, STMN2 is suppressed via activated proteasomal degradation, phosphorylation and translational repression by stress granules, independently of TDP-43 loss of function in splicing. We further show that STMN2 protein level is highly sensitive to chronic translation deficits, such as those elicited by prolonged low-grade stress. Finally, we demonstrate that STMN2 mRNA is upregulated in non-TDP ALS such as ALS-FUS, which may compensate for translation/stress granule defects in these disease subtypes. Consistent with the compensation hypothesis, STMN2 mRNA is also upregulated in the relatively spared (cortex), but not severely affected (spinal cord), CNS regions in ALS-TDP. In conclusion, our study implicates two common hallmarks of neurodegeneration, translation impairment and abnormal stress granules, in STMN2 depletion and reports an RNA-level compensation that fails in neurons with TDP-43 pathology. Our study supports the development of stress response targeting therapies in ALS with and without TDP-43 pathology.

cell biology↗

bioRxiv2024

Typical development of synaptic and neuronal properties can proceed without microglia

Brain-resident macrophages, microglia, have been proposed to play an active role in synaptic refinement and maturation, influencing plasticity and circuit-level connectivity. Here we show that a variety of neurodevelopmental processes previously attributed to microglia can proceed without them. Using a genetically modified mouse which lacks microglia (Csf1r{Delta}FIRE/{Delta}FIRE) we find that intrinsic properties, synapse number and synaptic maturation are largely normal in the hippocampal CA1 region and somatosensory cortex at stages where microglia have been implicated. Seizure susceptibility and hippocampal-prefrontal cortex coherence in awake behaving animals, processes disrupted in mice deficient in microglia-enriched genes, are also normal. Similarly, eye-specific segregation of inputs into the lateral geniculate nucleus proceeds normally in the absence of microglia. Single cell/nucleus transcriptomic analyses of neurons and astrocytes did not uncover any substantial perturbation due to microglial absence. Thus, the brain possesses remarkable adaptability to execute developmental synaptic refinement, maturation and connectivity in the absence of microglia.

neuroscience↗

bioRxiv2024

Landscape and meteorological variables associated with Aedes aegypti and Aedes albopictus mosquito infestation in two southeastern USA coastal cities

Aedes transmitted arboviral human cases are increasing worldwide and spreading to new areas of the United States of America (USA). These diseases continue to re-emerge likely due to changes in vector ecology, urbanization, human migration, and larger range of climatic suitability. Recent shifts in landscape and weather variables are predicted to impact the habitat patterns of urban mosquitoes such as Aedes aegypti and Aedes albopictus. Miami (FL) is in the tropical zone and an established hotspot for arboviruses, while Charleston (SC) is in the humid subtropical zone and newly vulnerable. Although these coastal cities have distinct climates, both have hot summers. To understand mosquito infestation in both cities and potentiate our surveillance effort, we performed egg collections in the warmest season. We applied remote sensing with land-use cover and weather variation to identify mosquito infestation patterns. Our study found predominant occurrence of Ae. aegypti and, to a lesser extent, Ae. albopictus in both cities. We detected statistically significant positive and negative associations between entomological indicators and most weather variables in combined data from both cities. For all entomological indices, weekly wind speed and relative humidity were significantly positively associated, while precipitation and maximum temperature were significantly negatively associated. Aedes egg abundance was significantly positively associated with open land in Charleston but was negatively associated with vegetation cover in combined data. There is a clear need for further observational studies to determine the impact of climate change on Ae. aegypti and Ae. albopictus infestation in the Southeastern region of the USA.

ecology↗

bioRxiv2023

Somatic Mosaicism in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Reveals Widespread Degeneration from Focal Mutations

Although mutations in many genes cause familial amyotrophic lateral sclerosis and frontotemporal dementia, most cases are sporadic (sALS and sFTD) with unclear etiology. We tested whether somatic mutations contribute to sALS and sFTD by deep targeted sequencing of 88 neurodegeneration-related genes in postmortem brain and spinal cord samples from 399 sporadic cases and 144 controls. Predicted deleterious somatic variants in ALS/FTD genes were observed in 2.1% of sporadic cases lacking deleterious germline variants. These variants occurred at very low allele fractions (typically <2%) and were often focal and enriched in disease-affected regions. Analysis of bulk RNA-seq data from an additional cohort identified deleterious somatic variants in DYNC1H1 and LMNA, genes associated with pediatric motor neuron degeneration. Targeted long-read sequencing further identified one sFTD case with de novo somatic C9orf72 repeat expansions. Together, these findings suggest that rare, focal somatic variants can contribute to sALS and sFTD and drive widespread neurodegeneration.

genetics↗

bioRxiv2023

Global Biogeography of the Soil Virosphere

Historically neglected by microbial ecologists, soil viruses are now thought to be critical to global biogeochemical cycles. However, our understanding of their global distribution, activities, and interactions with the soil microbiome remains limited. Here, we present the Global Soil Virus (GSV) Atlas, a comprehensive dataset compiled from 2,953 previously sequenced soil metagenomes and comprised of 616,935 uncultivated viral genomes (UViGs) and 38,508 unique viral operational taxonomic units (vOTUs). Rarefaction curves from the GSV Atlas indicate that most soil viral diversity remains unexplored, further underscored by high spatial turnover and low rates of shared vOTUs across samples. By examining genes associated with biogeochemical functions, we also demonstrate the viral potential to impact soil carbon and nutrient cycling. This study represents an extensive characterization of soil viral diversity and provides a foundation for developing testable hypotheses regarding the role of the virosphere in the soil microbiome and global biogeochemistry.

ecology↗

bioRxiv2023

Phylogeny, morphology, virulence, ecology, and host range of Ordospora pajunii (Ordosporidae),a microsporidian symbiont of Daphnia spp.

Impacts of microsporidia on host individuals are frequently subtle and can be context dependent. A key example of the latter comes from a recently discovered microsporidian symbiont of Daphnia, the net impact of which was found to shift from negative to positive based on environmental context. Given this, we hypothesized low baseline virulence of the microsporidian; here, we investigated the impact of infection on hosts in controlled conditions and the absence of other stressors. We also investigated its phylogenetic position, ecology and host range. The genetic data indicates that the symbiont is Ordospora pajunii, a newly described microsporidian parasite of Daphnia. We show that O. pajunii infection damages the gut, causing infected epithelial cells to lose microvilli and then rupture. The prevalence of this microsporidian could be high (up to 100% in the lab and 77% of adults in the field). Its overall virulence was low in most cases, but some genotypes suffered reduced survival and/or reproduction. Susceptibility and virulence were strongly host-genotype dependent. We found that North American O. pajunii were able to infect multiple Daphnia species, including the European species D. longispina, as well as Ceriodaphnia spp. Given the low, often undetectable virulence of this microsporidian, and potentially far reaching consequences of infections for the host when interacting with other pathogens or food, this Daphnia - O. pajunii symbiosis emerges as a valuable system for studying the mechanisms of context-dependent shifts between mutualism and parasitism, as well as for understanding how symbionts might alter host interactions with resources. ImportanceThe net outcome of symbiosis depends on the costs and benefits to each partner. Those can be context dependent, driving the potential for an interaction to change between parasitism and mutualism. Understanding the baseline fitness impact in an interaction can help us understand those shifts; for an organism that is generally parasitic, it should be easier for it to become a mutualist if its baseline virulence is relatively low. Recently, a microsporidian was found to become beneficial to its Daphnia hosts in certain ecological contexts, but little was known about the symbiont (including its species identity). Here, we identify it as the microsporidium Ordospora pajunii. Despite the parasitic nature of microsporidia, we found O. pajunii to be, at most, mildly virulent; this helps explain why it can shift towards mutualism in certain ecological contexts and helps establish O. pajunii is a valuable model for investigating shifts along the mutualism-parasitism continuum.

ecology↗

bioRxiv2022

Multi-block RNN Autoencoders Enable Broadband ECoG Signal Reconstruction

ObjectiveNeural dynamical models reconstruct neural data using dynamical systems. These models enable direct reconstruction and estimation of neural time-series data as well as estimation of neural latent states. Nonlinear neural dynamical models using recurrent neural networks in an encoder-decoder architecture have recently enabled accurate single-trial reconstructions of neural activity for neuronal spiking data. While these models have been applied to neural field potential data, they have only so far been applied to signal feature reconstruction (e.g. frequency band power), and have not yet produced direct reconstructions of broadband time-series data preserving signal phase and temporal resolution. ApproachHere we present two encoder-decoder model architectures - the RNN autoencoder (RAE) and multi-block RAE (MRAE) for direct time-series reconstruction of broadband neural data. We trained and tested models on multi-channel micro-Electricorticography (ECoG) recordings from non-human primate motor corticies during unconstrained behavior. Main ResultsWe show that RAE reconstructs micro-electrocorticography recordings, but has reconstruction accuracy that is band-limited to model scale. The MRAE architecture overcomes these time-bandwidth restrictions, yielding broadband (0-100 Hz), accurate reconstructions of ECoG data. SignificanceRAE and MRAE reconstruct broadband ECoG data through multiblock dynamical modeling. The MRAE overcomes time-bandwitdh restrictions to provide improved accuracy for long time duration signals. The reconstruction capabilities provided by these models for broadband neural signals like ECoG may enable the development of improved tools and analysis for basic scientific research and applications like brain-computer interfaces.

neuroscience↗

bioRxiv2020

Functional interaction between Fanconi anemia and mTOR pathways during stalled replication fork recovery

We have previously demonstrated that Fanconi Anemia (FA) proteins work in concert with other FA and non-FA proteins to mediate stalled replication fork restart. Previous studies suggest a connection between FA protein FANCD2 and a non-FA protein mechanistic target of rapamycin (mTOR). A recent study showed that mTOR is involved in actin-dependent DNA replication fork restart, suggesting possible roles in FA DNA repair pathway. In this study, we demonstrate that during replication stress mTOR interacts and cooperates with FANCD2 to provide cellular stability, mediates stalled replication fork restart and prevents nucleolytic degradation of the nascent DNA strands. Taken together, this study unravels a novel functional cross-talk between two important mechanisms: mTOR and FA DNA repair pathways that ensure genomic stability.

molecular biology↗

bioRxiv2019

Grid cells implement a location-dependent directional code

Grid and head direction codes represent cognitive spaces for navigation and memory. Pure grid cells generate grid codes that have been assumed to be independent of head direction, whereas conjunctive cells generate grid representations that are tuned to a single head direction. Here, we demonstrate that pure grid cells also encode head direction, but through distinct mechanisms. We show that individual firing fields of pure grid cells are tuned to multiple head directions, with the preferred sets of directions differing between fields. This local directionality is not predicted by previous continuous attractor or oscillatory interference models of grid firing but is accounted for by models in which pure grid cells integrate inputs from co-aligned conjunctive cells with firing rates that differ between their fields. Local directional signals from grid cells may contribute to downstream computations by decorrelating different points of view from the same location.

neuroscience↗

bioRxiv2019

Inter-animal variability, experience-dependence and continuous dorsoventral tuning of integrative properties of stellate cells in the medial entorhinal cortex

Distinctions between cell types underpin organisational principles for nervous system function. Functional variation also exists between neurons of the same type. This is exemplified by correspondence between grid cell spatial scales and synaptic integrative properties of stellate cells (SCs) in the medial entorhinal cortex. However, we know little about how functional variability is structured either within or between individuals. Using ex-vivo patch-clamp recordings from up to 55 SCs per mouse, we find that integrative properties vary between mice and, in contrast to modularity of grid cell spatial scales, have a continuous dorsoventral organisation. Our results constrain mechanisms for modular grid firing and provide evidence for inter-animal phenotypic variability among neurons of the same type. We suggest that neuron type properties are tuned to circuit level set points that vary within and between animals.

neuroscience↗

bioRxiv2018

Comparison of Two-Talker Attention Decoding from EEG with Nonlinear Neural Networks and Linear Methods

Auditory attention decoding (AAD) through a brain-computer interface has had a flowering of developments since it was first introduced by Mesgarani and Chang (2012) using electrocorticograph recordings. AAD has been pursued for its potential application to hearing-aid design in which an attention-guided algorithm selects, from multiple competing acoustic sources, which should be enhanced for the listener and which should be suppressed. Traditionally, researchers have separated the AAD problem into two stages: reconstruction of a representation of the attended audio from neural signals, followed by determining the similarity between the candidate audio streams and the reconstruction. In this work, we compare the traditional two-stage approach with a novel neural-network architecture that subsumes the explicit similarity step. We compare this new architecture against linear and non-linear (neural-network) baselines using both wet and dry electroencephalogram (EEG) systems. Our results indicate that the wet and dry systems can deliver comparable results despite the latter having one third as many EEG channels as the former, and that the new architecture outperforms the baseline stimulus-reconstruction methods for both EEG modalities. The 14-subject, wet-electrode AAD dataset for two competing, co-located talkers, the 11-subject, dry-electrode AAD dataset, and our software are available to download for further validation, experimentation, and modification.

neuroscience↗