Biology subjects

Monnet, H.

Publications and source records attributed to Monnet, H..

6 recordsLinked to original sources

bioRxiv2025

Local translation controls early reactive changes in perisynaptic astrocyte processes at pre-symptomatic stages of Alzheimer s disease

Early synaptic dysfunction is a hallmark of Alzheimers disease (AD), yet the astrocytic mechanisms underlying these alterations remain poorly defined. Here, we identify astrocyte perisynaptic processes (PAPs) as subcellular hotspots of early translational dysregulation in AD. Soluble A{beta}-2 rapidly enhanced global and local protein synthesis in primary astrocytes. In 5.5-month-old APP/PS1-dE9 (APP) mice, translating ribosome affinity purification (TRAP) revealed widespread remodeling of the PAP translatome, while whole-astrocyte translation remained largely unchanged. Dysregulated mRNAs were linked to neuroinflammation, synaptic remodeling, and endoplasmic reticulum stress, and alterations emerged prior to amyloid plaque deposition. Among them, Serpina3n exhibited increased mRNA abundance in PAPs, uncovering spatially restricted translational control. Mechanistically, early Serpina3n upregulation was partially driven by JAK-STAT3 signaling, with preferential effects in astrocyte processes. These findings reveal that local translation in astrocyte PAPs is an early and compartment-specific mechanism that may contribute to synaptic dysfunction and disease initiation in AD.

neuroscience↗

bioRxiv2025

Interactions of the LINE-1 encoded ORF1p with proteins and chromatin converge on a role in neuronal physiology

Retrotransposons are emerging as novel regulators of embryonic and brain development. We recently demonstrated that the LINE-1-encoded protein ORF1p is abundantly expressed in adult mouse and human neurons, although its function remains unclear. Here, we characterize the ORF1p interactome in differentiated mouse and human neurons using mass spectrometry and identify novel partners implicated in gene regulation and neuron-specific processes. ORF1p localizes not only to neuronal nuclei, where it associates with chromatin under steady-state conditions, but also to neurites, supporting a role in neuronal physiology. To further explore its nuclear functions, we sorted human post-mortem neurons with high or low nuclear ORF1p levels and performed ORF1p knockdown in cultured human neurons, followed by chromatin accessibility assays. Both approaches revealed consistent patterns of differential chromatin accessibility dependent on ORF1p. Loss of ORF1p also led to the downregulation of long, neuron-specific genes and altered neurite morphology. Together, these findings point to a physiological role of ORF1p in post-mitotic neurons, mediated through converging interactions with proteins and chromatin.

neuroscience↗

bioRxiv2025

VeCell: A Fiji Plugin to unveil the spatio-temporal dynamics of macroglial cell development and proximity to blood vessels

Brain cortical development results from the proliferation, differentiation, migration and maturation of many cell types. While neuronal development is well characterized, the mechanisms regulating macroglial cells (oligodendrocytes and astrocytes) development remain largely unknown. Recent works suggest that the vascular system plays a key, yet under-evaluated role in this process. In this study, we investigated the spatial organization of macroglial cells within the parenchyma and relative to blood vessels. Using immunolabeling for Sry-box transcription factor (Sox) 9 (macroglial progenitors and astrocytes) and Sox10 (oligodendrocyte lineage), we determined macroglia density, distribution and proximity to blood vessels from postnatal day (P) 1 to P60 in the somatosensory cortex. We showed that Sox9+ cells were evenly distributed across cortical layers with regular intercellular spacing. In contrast, Sox10+ cells concentrated in deeper cortical layers, and exhibited a random distribution. Vascular density and branching increased markedly between P5 and P15 and macroglial cells were closer to blood vessels from P15 onward. We investigated possible alteration of astrocyte distribution in the cortex of MLC1-deficient mice, a model of Megalencephalic leukoencephalopathy with subcortical cysts, in which astrocyte perivascular coverage is altered. No difference with the control condition were found both in young and adult mice, either in the density, distribution or distance to blood vessels. Altogether, we revealed distinct distribution and postnatal development patterns for astrocytes and oligodendrocytes in the brain and in relation to the vasculature. Table of Contents Entry O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/632893v3_ufig1.gif" ALT="Figure 1"> View larger version (66K): org.highwire.dtl.DTLVardef@10ab9f2org.highwire.dtl.DTLVardef@135c06dorg.highwire.dtl.DTLVardef@1ec4f65org.highwire.dtl.DTLVardef@1509f08_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LIFrom P5, Sox9 cells are evenly distributed, unlike Sox10 cells C_LIO_LIFrom P15, Sox9 cells are located closer to blood vessels than Sox10 cells C_LIO_LIDistribution of astrocytes is not altered in Mlc1 KO cortex C_LI

neuroscience↗

bioRxiv2023

Steady-state neuron-predominant LINE-1 encoded ORF1p protein and LINE-1 RNA increase with aging in the mouse and human brain

Recent studies have established a reciprocal causal link between aging and the activation of transposable elements, characterized in particular by a de-repression of LINE-1 retrotransposons. These LINE-1 elements represent 21% of the human genome, but only a minority of these sequences retain the coding potential essential for their mobility. LINE-1 encoded proteins can induce cell toxicity implicated in aging and neurodegenerative diseases. However, our knowledge of the expression and localization of LINE-1-encoded proteins in the central nervous system is limited. Using a novel approach combining atlas-based brain mapping with deep-learning algorithms on large-scale pyramidal brain images, we unveil a heterogeneous, neuron-predominant and widespread ORF1p expression throughout the murine brain at steady-state. In aged mice, ORF1p expression increases significantly which is corroborated in human post-mortem dopaminergic neurons by an increase in young LINE-1 elements including those with open reading frames. Mass spectrometry analysis of endogenous mouse ORF1p revealed novel, neuron-specific protein interactors. These findings contribute to a comprehensive description of the dynamics of LINE-1 and ORF1p expression in the brain at steady-state and in aging and provide insights on ORF1p protein interactions in the brain.

neuroscience↗

bioRxiv2023

Nuclear translocation of LINE-1 ORF1p alters nuclear envelope integrity and disrupts nucleocytoplasmic transport in neurons

LINE-1 retrotransposons are emerging as possible culprits in neurodegenerative diseases. However, the molecular mechanisms underlying the pathogenic role of LINE-1 and their encoded proteins ORF1p and ORF2p are still not completely understood. While the endonuclease and reverse transcriptase activities of ORF2p have been associated with DNA damage and inflammation, no pathogenic role has yet been assigned to ORF1p. Using a neuronal model of oxidative stress displaying increased LINE-1 expression, we report here that ORF1p stress-dependently translocated into the nucleus, localized to the nuclear envelope and directly interacted with nuclear import proteins, nuclear pore complex components and the inner nuclear lamina. Stress-dependent targeting of nuclear envelope components by ORF1p altered nuclear envelope integrity, disrupted nucleocytoplasmic transport and induced heterochromatin destructuration, features associated with neurodegenerative diseases and aging. Neurons of post-mortem Parkinson disease (PD) patients and non-PD affected controls expressed ORF1p and nuclear ORF1p levels correlated with altered nuclear shape in PD. Overexpression of ORF1p in neurons in the absence of stress recapitulated nuclear envelope dysfunctions and increased nuclear ORF1p levels correlated with a loss of nuclear circularity. Stress-induced nuclear alterations were restored by blocking ORF1p nuclear import or by the small molecule remodelin. This study thus reveals a retrotransposition- and ORF2p- independent pathogenic action of ORF1p at the nuclear envelope and points to ORF1p as a novel target for neuroprotection.

neuroscience↗

bioRxiv2023

Dynamic local mRNA distribution and translation influence the postnatal molecular maturation of perivascular astrocytic processes

Astrocytes (the main glial cells in the brain) are highly ramified and send out perivascular processes (PvAPs) that entirely sheathe the brains blood vessels. PvAPs are equipped with an enriched molecular repertoire that sustains astrocytic regulatory functions at the vascular interface. In the mouse, PvAP development starts after birth and is essentially complete by postnatal day (P) 15. Progressive molecular maturation also occurs over this period, with the acquisition of proteins enriched in PvAPs. The mechanisms controlling the development and molecular maturation of PvAPs have not been extensively characterized. We reported previously that mRNAs are distributed unequally in mature PvAPs and are locally translated. Since dynamic mRNA distribution and local translation influence the cells polarity, we hypothesized that they might sustain the postnatal maturation of PvAPs. Here, we used a combination of molecular biology and imaging approaches to demonstrate that the development of PvAPs is accompanied by the transport of mRNA and polysomal mRNA into PvAPs, the development of a rough endoplasmic reticulum (RER) network and Golgi cisternae, and local translation. By focusing on genes and proteins that are selectively or specifically expressed in astrocytes, we characterized the developmental profile of mRNAs, polysomal mRNAs and proteins in PvAPs from P5 to P60. Furthermore, we found that distribution of mRNAs in PvAPs is perturbed in a mouse model of megalencephalic leukoencephalopathy with subcortical cysts. Lastly, we found that some polysomal mRNAs polarized progressively towards the PvAPs. Our results indicate that dynamic mRNA distribution and local translation influence the postnatal maturation of PvAPs. Summary statementLocal translation operates during the postnatal development of perivascular astrocyte processes and might contribute to their molecular maturation.

neuroscience↗