Biology subjects

Guillermier, M.

Publications and source records attributed to Guillermier, M..

5 recordsLinked to original sources

bioRxiv2026

Acetylcholine drives astrocytic JAK2-STAT3 signaling to modulate male-to-female approach behavior

Astrocytes are essential regulators of neural circuits and behavior, sensing synaptic activity and modulating plasticity through diverse intracellular mechanisms. However, the contribution of astrocyte transcription factor-based cascades, linking external stimuli to long-term transcriptional programs, is currently misunderstood. Here we show that the JAK2-STAT3 signaling plays a critical role in male-to-female social behavior. Hence, in male mice, exposure to estrus females rapidly and selectively induces STAT3 signaling in ventral hippocampal astrocytes. Surprisingly, this induction is not driven through canonical cytokine signaling but by septo-hippocampal cholinergic inputs acting through 7 nicotinic acetylcholine receptors (7nAChR). Astrocytic 7nAChR-JAK2-STAT3 signaling in turn modulates vCA1 pyramidal neuron activity and is required for context-appropriate male approach behavior. These findings reveal a previously unsuspected cellular pathway integrating neuromodulatory inputs and transcription factor-based signaling to shape male behavioral response depending on female receptivity.

neuroscience↗

bioRxiv2026

Brain-specific PP1/LRRK2 interaction-targeting peptides as a novel strategy for Parkinson's disease treatment

The LRRK2 kinase has emerged as a priority therapeutic target due to its well-documented role in Parkinson-s diseases (PD). One of LRRK2s key partners is the phosphatase PP1, which dephosphorylates LRRK2. Therefore, modulating this protein/protein interaction represents a promising therapeutic strategy for PD. We have developed a bi-functional peptide, PEP 3, capable of crossing the blood-brain barrier (BBB) and disrupting the LRRK2/PP1 interaction. In vitro competition assays confirmed that PEP 3 specifically targets this interaction. The in vivo imaging demonstrated that the peptide remains detectable in the mouse brain up to 6 hours or retro-orbital vein post-injection. The PEP 3 peptide does not show chronic toxicity in CD1 mice and is resistant to degradation by mouse, human, dog and monkey serum proteases. In mouse models overexpressing alpha-synuclein, repeated intraperitoneal injections of PEP 3 for 15 and 30 days were well tolerated. Immunohistochemistry revealed a significant reduction of dopaminergic cell death in the substantia nigra, and quantification of phosphorylated pathological alpha-synuclein showed decreased levels in the PEP 3-treated group compared to controls. These findings support the potential of PEP 3 as a therapeutic agent for Parkinsons disease.

neuroscience↗

bioRxiv2025

AAV-mediated allele-specific silencing alleviates neuropathology in a novel non-human primate model of Spinocerebellar ataxia type 3

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is an autosomal dominant neurodegenerative disorder caused by an abnormal expansion of the cytosine-adenine-guanine (CAG) repeats in the ATXN3 gene. This mutation results in the production of an Ataxin-3 protein with an extended polyglutamine sequence, contributing to the diseases neuropathology. Currently, no treatment is available that can slow or halt the progression of SCA3. Gene-targeted therapies have gained significant attention for their potential to address the root cause of SCA3. Preliminary studies in transgenic mice using adeno-associated viral vector serotype 9 (AAV9) encoding artificial microRNAs targeting the mutant ATXN3 allele (AAV9-miR-ATXN3) have shown promising results. However, to advance this therapeutic approach toward clinical application, further studies in an animal model that more closely resembles human biology are essential. In this exploratory study, we assessed the biodistribution and target engagement of AAV9-miR-ATXN3 delivered via intracisterna magna (ICM) injection in non-human primates (NHPs). Using a lentiviral vector (LV) to introduce a mutant Ataxin-3 cDNA with 72 glutamines (LV-mutATXN3-Q72) into the NHP cerebellum, we successfully overexpressed SCA3 in the NHP brain. SCA3 NHP exhibited Ataxin-3 aggregation in the cerebellum, recruitment of inflammatory cells and reduced cerebellar volume. ICM administration of AAV9-miR-ATXN3 effectively directed transgene expression to key brain regions impacted by SCA3 pathology and enabled specific, dose-dependent silencing of mutant Ataxin-3. Furthermore, the therapeutic dose prevented the cerebellar morphological and biochemical alterations induced by the overexpression of mutant ATXN3. These proof-of-concept experiments are crucial, not only for advancing AAV9-miR-ATXN3 toward clinical use but also for establishing a valuable platform for validating future therapeutic interventions.

molecular biology↗

bioRxiv2021

The JAK2-STAT3 pathway controls a beneficial proteostasis response of reactive astrocytes in Huntington disease

Huntingtons disease is a fatal neurodegenerative disease characterized by striatal neurodegeneration, aggregation of mutant Huntingtin and the presence of reactive astrocytes. Astrocytes are important partners for neurons and engage in a specific reactive response in Huntingtons disease that involves morphological, molecular and functional changes. How reactive astrocytes contribute to Huntingtons disease is still an open question, especially because their reactive state is poorly reproduced in experimental mouse models. Here, we show that the JAK2-STAT3 pathway, a central cascade controlling astrocyte reactive response, is activated in the putamen of Huntingtons disease patients. Selective activation of this cascade in astrocytes through viral gene transfer reduces the number and size of mutant Huntingtin aggregates in neurons and improves neuronal defects in two complementary mouse models of Huntingtons disease. It also reduces striatal atrophy and increases glutamate levels, two central clinical outcomes measured by non-invasive magnetic resonance imaging. Moreover, astrocyte-specific transcriptomic analysis shows that activation of the JAK2-STAT3 pathway in astrocytes coordinates a transcriptional program that increases their intrinsic proteolytic capacity, through the lysosomal and ubiquitin-proteasome degradation systems. This pathway also enhances their production and exosomal release of the co-chaperone DNAJB1, which contributes to mutant Huntingtin clearance in neurons. Together, our results show that the JAK2-STAT3 pathway controls a beneficial proteostasis response in reactive astrocytes in Huntingtons disease, which involves bi-directional signalling with neurons to reduce mutant Huntingtin aggregation, eventually improving disease outcomes.

neuroscience↗

bioRxiv2019

Complex roles for reactive astrocytes in the triple transgenic mouse model of Alzheimer disease

In Alzheimer disease (AD), astrocytes undergo complex changes and become reactive. The consequences of this reaction are still unclear. To evaluate the net impact of reactive astrocytes in AD, we recently developed viral vectors targeting astrocytes that either activate or inhibit the JAK2-STAT3 pathway, a central cascade controlling astrocyte reaction.\n\nWe aimed to evaluate whether reactive astrocytes contribute to Tau as well as amyloid pathologies in the hippocampus of 3xTg-AD mice, an AD model that develops Tau hyperphosphorylation and aggregation in addition to amyloid deposition. JAK2-STAT3 pathway-mediated modulation of reactive astrocytes in the hippocampus of 3xTg-AD mice, did not significantly influence Tau phosphorylation or amyloid processing and deposition, at early, advanced and terminal stage of the disease. Interestingly, inhibition of the JAK2-STAT3 pathway in hippocampal astrocytes did not improve short-term spatial memory in the Y maze but it reduced anxiety in the elevated plus maze. Our unique approach to specifically manipulate reactive astrocytes in situ show these cells may impact behavioral outcomes without influencing Tau or amyloid pathology.

neuroscience↗