Biology subjects

Rose, M.

Publications and source records attributed to Rose, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Diabetes impacts endothelial Weibel-Palade body biogenesis and VWF secretion

Diabetes is associated with endothelial dysfunction, impaired wound healing, and increased thrombotic risk, yet the impact of diabetes on endothelial secretory organelles remains poorly understood. Weibel-Palade bodies (WPBs) are specialised endothelial granules that store and release von Willebrand factor (VWF) and other vasoactive cargo essential for haemostasis, inflammation, and vascular repair. Here, we investigated how diabetic environments influence WPB biogenesis and VWF structure under physiologically relevant flow conditions. Acute exposure of endothelial cells to constant or fluctuating high glucose concentrations, designed to model diabetic glycaemic conditions, did not alter WPB number or morphology under either static or high laminar shear stress conditions. In contrast, primary endothelial cells derived from a diabetic donor exhibited reduced Akt and eNOS signalling, significantly fewer WPBs, reduced intracellular VWF content, and shorter stimulus-evoked VWF strings compared with non-diabetic endothelial cells. Although total cellular VWF levels were reduced, high molecular weight (HMW) VWF content within endothelial lysates was not significantly altered. Plasma from diabetic patients demonstrated elevated circulating VWF levels together with marked inter-patient heterogeneity in VWF multimer composition. These findings suggest that chronic diabetes-associated endothelial dysfunction, rather than hyperglycaemia alone, alters WPB biology and VWF handling. We propose that dysregulated basal endothelial secretion may deplete endothelial VWF stores, limiting appropriate stimulus-coupled WPB release during vascular injury and contributing to defective vascular repair in diabetes.

cell biology↗

bioRxiv2026

Oncogenic Ras-Src-cortactin signaling rewires actin-generated forces to drive basement membrane rupture and initiate breast cancer invasion

Oncogenic HRas activation plays a fundamental role in tumorigenesis, yet the cellular mechanisms by which HRas downstream signaling drives basement membrane (BM) disruption during early breast cancer invasion remain unclear. Using HRas-inducible breast spheroids, we demonstrate that HRas rewires cellular mechanotransduction of tumor-associated extracellular matrix stiffening to promote invasion. This process occurs independently of canonical myosin II-mediated contractility and proteolytic BM degradation. Transcriptomic and kinome profiling identified an HRas-Src-cortactin-Arp2/3 signaling axis that generates disruptive mechanical BM stress. We describe cortical triplet (CT) structures, defined by cortactin-dependent actin reinforcement and localized BM loss. CTs integrate increased cortical tension, actin polymerization forces, and myosin I-dependent contractility, thereby predicting invasion events. Pharmacological inhibition of Src or Arp2/3 reduced CT formation and invasion. Furthermore, elevated expression of HRas-cortactin-Arp2/3 axis components correlated with poor patient survival. Together, these findings uncover a previously unrecognized mechanism of early breast cancer invasion and highlight potential therapeutic targets.

cancer biology↗

bioRxiv2026

A light-labile signal molecule acts as a photoregulator of secondary metabolite biosynthesis in a heterotrophic bacterium

While light is essential for many phototrophic organisms, our knowledge of the light-dependent regulation in heterotrophic organisms is scarce. Here, we found that the heterotrophic soil bacterium Pseudomonas protegens differentially accumulated 234 secreted metabolites depending on the light conditions. These metabolites included important antimicrobials such as pyoluteorin, 2,4-diacetylphloroglucinol, pyrrolnitrin, and rhizoxin analogs. Pyoluteorin, for instance, was 140-fold more abundant in the dark, due to a strong upregulation of the transcript of the pyoluteorin biosynthesis gene pltL. We discovered that 2,4-dichlorophloroglucinol (PG-Cl2), an activator of pyoluteorin biosynthesis, acts as a photoregulator that degrades much faster in the presence of light than in the dark. The resulting higher PG-Cl2 levels activate the pltL promoter in the dark. These findings reveal a novel mode of regulation in which light instability of a signal molecule allows the producing organism to sense and transmit light information to regulate the biosynthesis of a secondary metabolite.

microbiology↗

bioRxiv2025

Differential Cerebral White Matter Tract Alterations in Generalized Anxiety Disorder Revealed by Ultra-High Field 7T Diffusion-Weighted Imaging

BackgroundGeneralized anxiety disorder (GAD) is characterized by chronic worry and emotional dysregulation, yet its underlying white matter (WM) architecture remains inconsistent in previous neuroimaging studies. This study aimed to delineate microstructural WM alterations in GAD using ultra-high field (7T) diffusion tensor imaging (DTI) and advanced correlational tractography, evaluating their associations with symptom severity and diagnostic-aided value. MethodsEighty-eight participants (27 GAD, 61 healthy controls, HCs) underwent 7T DTI scanning with 1.5-mm isotropic resolution. Whole-brain correlational tractography was applied to identify tracts exhibiting significant group-related differences in diffusion indices while controlling for demographic covariates. Associations with Hamilton Anxiety Rating Scale (HAM-A) and Penn State Worry Questionnaire (PSWQ) scores were examined, and machine learning-based models were used to assess the diagnostic-aided utility of identified WM features. ResultsTwo tract bundles showed significant fractional anisotropy (FA) alterations in GAD: decreased FA in the right prefrontal pathway (PFDR = 0.039) and increased FA in the right cingulum (PFDR < 0.001). The anterior portions of both tracts exhibited stronger effects of GAD. FA in the right cingulum positively correlated with HAM-A and PSWQ scores, indicating that greater microstructural coherence was associated with higher anxiety and worry severity (both PFDRs < 0.001). Inclusion of WM features could improve classification performance beyond neuropsychological measures alone. ConclusionsUltra-high field 7T tractometry revealed a differential pattern of WM abnormalities in GAD, suggesting weakened prefrontal control and hyper-integrated cingulate connectivity as structural correlates of emotional dysregulation. These findings indicate the potential of 7T DTI markers for advancing mechanistic and diagnostic understanding of GAD.

neuroscience↗

bioRxiv2025

Ovarian Tumor FAK Inhibition Releases Omega-3 Fatty Acids Stimulating GATA6 Peritoneal Macrophage CXCL13 Production Enhancing Immunotherapy

High grade serous ovarian cancer (HGSOC) is the most lethal gynecologic malignancy in the USA due to chemo- and immuno-therapy resistance. We show that focal adhesion kinase (FAK) inhibition with ifebemtinib or tumor genetic FAK knockout (KO) in syngeneic ovarian tumor models stimulated resident large peritoneal macrophages to express CXCL13 chemokine and promoted B cell infiltration. Macrophage GATA6 inactivation prevented CXCL13 expression and enhanced FAK-KO tumor growth. Combining ifebemtinib with pegylated doxorubicin chemotherapy and anti-TIGIT immune checkpoint antibody extended survival with tumor-associated tertiary lymphoid structure formation. Mechanistically, FAK-KO heat-treated conditioned media contained exosomes enriched with omega-3 fatty acids which stimulated macrophage CXCL13 production. Ifebemtinib-treated tumors, FAK-KO exosomes, and purified eicosapentaenoic acid enhanced murine and human HGSOC-associated tumor macrophage reprogramming and CXCL13 expression. Overall, our studies define a tumor to macrophage signaling linkage via omega-3 exosome lipids supporting B cell recruitment, survival, immunotherapy enhancement, and actionable via small molecule FAK inhibition. eTOC BlurbHigh-grade serous ovarian cancer remains difficult to treat due to therapy resistance. Chen et. al. reveal that tumor FAK inhibition educates macrophages to express CXCL13 associated with B cell infiltration - highlighting a new therapeutic pathway linking FAK inhibition, omega-3 fatty acid containing exosomes, and macrophage mediated anti-tumor activation. Bullet pointsO_LIGenetic or small molecule FAK inhibition enhances ovarian tumor B cell infiltration C_LIO_LITumor FAK inhibition stimulates GATA6+ macrophages to make CXCL13 C_LIO_LIFAKi, pegylated doxorubicin and anti-TIGIT promote tertiary lymphoid structures C_LIO_LIOmega-3 fatty acids stimulate human HGSOC ascites macrophages to make CXCL13 C_LI

cancer biology↗

bioRxiv2025

Two-pore channel protein 2-mediated calcium release promotes angiopoietin 2 secretion by regulating Rab46-dependent Weibel-Palade body trafficking

Angiopoietin2 (Ang2), a regulator of angiogenesis, is stored with other pro-inflammatory and pro-thrombotic mediators, in endothelial-specific vesicles called Weibel-Palade bodies (WPBs). The WPB secretagogue, histamine, delays Ang2 secretion by activating Rab46-specific trafficking of Ang2-positive WPBs to the microtubule organising centre (MTOC), where they persist until Ca2+ binds to the EF-hand of Rab46, enabling detachment. Here, using Ca2+ imaging and high-resolution light microscopy, we pharmacologically investigated the contribution of endolysosomal two-pore channels proteins (TPC) to the Ca2+ signal necessary for Ang2 secretion. We show an increase in the histamine-evoked clustering of Rab46 (and thus WPBs) at the MTOC in the presence of TPC inhibitors Ned19 and tetrandrine, and a decrease in the presence of a TPC2 agonist, TPC2-A1-N. Histamine-evoked secretion of Ang2 was decreased by pharmacological inhibition of TPC channels but potentiated in the presence of an TPC2 agonist. These data suggest that histamine-mediated Ca2+ release via TPC2 channels is necessary for the Rab46-dependent detachment of Ang2-positive WPBs from the MTOC and thus Ang2 secretion. SummaryCa2+ binding to the EF-hand of Rab46 in endothelial cells has previously been reported but the molecular mechanisms and functional relevance is unclear. Here the authors show that Ca2+ released from TPC2 regulates the detachment of Rab46 from the MTOC and thereby allows secretion of Ang2 from WPBs.

cell biology↗

bioRxiv2024

Retrospective Analysis of the Effects of BWF Interdisciplinary Postdoctoral to Faculty Transition Awards on Future Funding Success

Established by the Burroughs Wellcome Fund (BWF) in 2001, the Career Award at the Scientific Interface (CASI) is a career development award for scientists with doctoral training in the physical/mathematical/computational sciences or engineering conducting postdoctoral research in the biological sciences. The goal of the program is to support early career scientists interested in pursuing an independent research career with an interdisciplinary focus. In order to assess the benefit of the CASI award on recipients, the authors undertook a retrospective analysis of the funding data for CASI recipients to evaluate success against matching cohorts. These cohorts included applicants who succeeded to the final interview stage but were ultimately unsuccessful (interviewed), applicants who submitted proposals but did not make it to the final interview stage (proposal declined), and a randomly selected dataset of researchers from a comparable program, the highly competitive Pathway to Independence Award (K99/R00) from the National Institutes of Health (NIH). The results indicate that CASI recipients outperformed unsuccessful applicants and their K99/R00 counterparts in federal grant rates and overall grant dollars. The authors conclusion affirms that the CASI mechanism and BWF support successfully achieve the objective of invigorating the careers of young investigators, resulting in tangible downstream long-term effects.

scientific communication and education↗

bioRxiv2024

The neural dynamics of positive and negative expectations of pain

Pain is heavily modulated by expectations. Whereas the integration of expectations with sensory information has been examined in some detail, little is known about how positive and negative expectations are generated and their neural dynamics from generation over anticipation to the integration with sensory information. The present preregistered study employed a novel paradigm to induce positive and negative expectations on a trial-by-trial basis and examined the neural mechanisms using combined EEG-fMRI measurements (n=50). We observed substantially different neural representations between the anticipatory and the actual pain period. In the anticipation phase i.e., before the nociceptive input, the insular cortex, dorsolateral prefrontal cortex (DLPFC), and anterior cingulate cortex (ACC) showed increased activity for directed expectations regardless of their valence. Interestingly, a differentiation between positive and negative expectations within the majority of areas only occurred after the arrival of nociceptive information. FMRI-informed EEG analyses could reliably track the temporal sequence of processing showing an early effect in the DLPFC, followed by the anterior insula and late effects in the ACC. The observed effects indicate the involvement of different expectation-related subprocesses, including the transformation of visual information into a value signal that is maintained and differentiated according to its valence only during stimulus processing.

neuroscience↗

bioRxiv2023

Transgene-Free Ex Utero Derivation of A Human Post-Implantation Embryo Model Solely from Genetically Unmodified Naive PSCs

Our ability to study early human post-implantation development remains highly limited due to the ethical and technical challenges associated with intrauterine development of the human embryo after implantation. Despite the great progress made on human gastruloids, axioloids and in vitro cultured blastoids, such elegant models do not constitute an integrated Stem cell-derived Embryo Models (SEMs) that includes all the key extra-embryonic tissues of the early post-implantation human conceptus (e.g., hypoblast, yolk-sac, trophoblasts, amnion, and extraembryonic mesoderm), and thus, do not recapitulate post-implantation epiblast development within the context of these extra-embryonic compartments. Mouse naive pluripotent stem cells (PSCs) have recently been shown to give rise to embryonic and extra-embryonic stem cells capable of self-assembling into post-gastrulation mouse SEMs, while bypassing the blastocyst-like stage, and eventually initiating organogenesis ex utero. Here, we implement critical adaptations to extend these finding to humans, while using only genetically unmodified human naive PSCs, thus circumventing the need for ectopic expression of lineage promoting transgenes. Such integrated human SEMs recapitulate the organization of all known compartments of early post-implantation stage human embryos, including epiblast, hypoblast, extra-embryonic mesoderm, and trophoblast surrounding the latter layers. The organized human SEMs recapitulate key hallmarks of post-implantation stage embryogenesis up to 13-14 days post-fertilization (dpf, Carnegie stage 6a), such as bilaminar disk formation, epiblast lumenogenesis, amniogenesis, anterior-posterior symmetry breaking, PGC specification, primary and secondary yolk sac formation, and extra-embryonic mesoderm expansion that defines a chorionic cavity and a connective stalk. This new platform constitutes a tractable stem cell-based model for experimentally interrogating previously inaccessible windows of human peri- and early post-implantation development.

developmental biology↗

bioRxiv2022

Agency and Expectations in Pain Treatment: An Investigation of the Active Inference Model

The fact that we cannot tickle ourselves is traditionally explained by the attenuation of somatosensation by predictions from a forward model of self-generated movements. Alternatively, it has been suggested within the framework of active inference that Bayes-optimal reduction of sensory precision can explain this phenomenon. Combining a pain paradigm with stimulus-related expectations allows to compare both models through predictions from the Bayesian account of expectation-based hypoalgesia, where pain is influenced by the precisions of somatosensation and expectation. In two experiments, heat pain was sham-treated either externally or by the subject, while a cue created higher or lower treatment expectations. Both experiments revealed greater pain relief under self-treatment and high treatment expectations. Electroencephalography revealed a modulation of theta-to-beta frequencies linked to agency and top-down modulations of pain perception. Computational modeling showed that this is better explained by an attenuation of somatosensation than a downregulation of somatosensation precision, favoring the forward model.

neuroscience↗

bioRxiv2022

SPAG6 promotes cell migration and induces epithelial-to-mesenchymal transition in luminal breast cancer cells

Understanding the involvement of promoter DNA methylation changes in the development of breast cancer may be highly informative for designing more effective therapeutic treatments. We recently characterized the Sperm Associated Antigen 6 (SPAG6) gene, encoding a flagellar motility protein, as a potential DNA methylation biomarker for blood-based early breast cancer detection. Here we present the first study to evaluate the functional role of SPAG6 in human breast cancer. In silico analysis of the HumanMethylation450 BeadChip and Illumina HiSeq data of The Cancer Genome Atlas (TCGA) was performed in both normal (n=114) and breast cancer patient tissues (n=1104) to determine SPAG6 DNA methylation and expression. Stable SPAG6 overexpressing cancer models for in vitro analysis were obtained by lentivirus-mediated gene delivery in T-47D, MCF-7, MDA-MB-231 and BT-549 breast cancer cells. Subsequently stable mock and SPAG6 cell lines were compared in cellular assays. In addition, involvement of SPAG6 in EMT was analysed by qPCR and immunolabeling experiments. All major molecular subtypes of breast cancer (luminal A, luminal B, basal-type, HER2-enriched) revealed a tumor-specific increased SPAG6 promoter hypermethylation that correlated with strong reduction in SPAG6 mRNA expression. Interestingly, a small group of luminal breast tumors exhibited SPAG6 mRNA overexpression compared to normal breast tissue. SPAG6 overexpression caused a significant reduction (p<0.05) in colony formation in basal MDA-MB-231 and BT-549 cells. In turn, luminal T-47D cells overexpressing SPAG6 showed a significant increase in colony formation (p=0.0004) and both T-47D-and MCF-7 cells overexpressing SPAG6 exhibited a robust increase in migration speed (p<0.0001). In SPAG6-positive T-47D cells SNAIL, TWIST1 and Vimentin expression was found to be significantly upregulated, while E-Cadherin expression was supressed. SPAG6 overexpressing T47D cells showed a typical epithelial-mesenchymal transition (EMT). This was accompanied by a nearly complete displacement of both actin and E-cadherin from cell-cell junctions. Our in vitro analyses give functional evidence that SPAG6 has a profound effect on colony formation, migration and intercellular junction composition in breast cancer cells. Our study is the first to show opposing SPAG6 effects in a single tumour entity depending on the molecular subtype. We propose that SPAG6 might be a key player for inducing the EMT program in luminal-type breast cancers, driving tumour progression and metastasis.

cell biology↗

bioRxiv2022

Observation of a single protein by ultrafast X-ray diffraction

The idea of using ultrashort X-ray pulses to obtain images of single proteins frozen in time has fascinated and inspired many. It was one of the arguments for building X-ray free-electron lasers. According to theory1, the extremely intense pulses provide sufficient signal to dispense with using crystals as an amplifier, and the ultrashort pulse duration permits capturing the diffraction data before the sample inevitably explodes2. This was first demonstrated on biological samples a decade ago on the giant mimivirus3. Since then a large collaboration4 has been pushing the limit of the smallest sample that can be imaged5,6. The ability to capture snapshots on the timescale of atomic vibrations, while keeping the sample at room temperature, may allow probing the entire conformational phase space of macromolecules. Here we show the first observation of an X-ray diffraction pattern from a single protein, that of Escherichia coli GroEL which at 14 nm in diameter7 is the smallest biological sample ever imaged by X-rays, and demonstrate that the concept of diffraction before destruction extends to single proteins. From the pattern, it is possible to determine the approximate orientation of the protein. Our experiment demonstrates the feasibility of ultrafast imaging of single proteins, opening the way to single-molecule time-resolved studies on the femtosecond timescale.

biophysics↗

bioRxiv2022

SARS-CoV-2 triggers Golgi fragmentation via downregulation of GRASP55 to facilitate viral trafficking

The COVID-19 pandemic is caused by SARS-CoV-2, an enveloped RNA virus. Despite extensive investigation, the molecular mechanisms for its assembly and secretion remain largely elusive. Here, we show that SARS-CoV-2 infection induces global alterations of the host endomembrane system, including dramatic Golgi fragmentation. SARS-CoV-2 virions are enriched in the fragmented Golgi. Disrupting Golgi function with small molecules strongly inhibits viral infection. Significantly, SARS-CoV-2 infection down-regulates GRASP55 but up-regulates TGN46 protein levels. Surprisingly, GRASP55 expression reduces both viral secretion and spike number on each virion, while GRASP55 depletion displays opposite effects. In contrast, TGN46 depletion only inhibits viral secretion without affecting spike incorporation into virions. TGN46 depletion and GRASP55 expression additively inhibit viral secretion, indicating that they act at different stages. Taken together, we show that SARS-CoV-2 alters Golgi structure and function to control viral assembly and secretion, highlighting the Golgi as a potential therapeutic target for blocking SARS-CoV-2 infection.

cell biology↗

bioRxiv2021

Alpha-to-beta- and gamma-band activity reflect predictive coding in affective visual processing

Processing of negative affective pictures typically leads to desynchronization of alpha-to-beta frequencies (ERD) and synchronization of gamma frequencies (ERS). Given that in predictive coding higher frequencies have been associated with prediction errors, while lower frequencies have been linked to expectations, we tested the hypothesis that alpha-to-beta ERD and gamma ERS induced by aversive pictures are associated with expectations and prediction errors, respectively. We recorded EEG while volunteers were involved in a probabilistically cued affective picture task using three different negative valences to produce expectations and prediction errors. Our data show that alpha-to-beta band activity was related to the expected valence of the stimulus as predicted by a cue. The absolute mismatch of the expected and actual valence, which denotes an absolute prediction error was related to gamma band activity. This demonstrates that top-down predictions and bottom-up prediction errors are represented in specific spectral patterns associated with affective picture processing.

neuroscience↗

bioRxiv2020

The temporal characteristics of expectations and prediction errors in pain

In the context of a generative model, such as predictive coding, pain and heat perception can be construed as the integration of expectation and input with their difference denoted as a prediction error. In a previous neuroimaging study (Geuter et al., 2017) we observed an important role of the insula in such a model, but could not establish its temporal aspects. Here we employed electroencephalography to investigate neural representations of predictions and prediction errors in heat and pain processing. Our data show that alpha-to-beta activity was associated with stimulus intensity expectation, followed by a negative modulation of gamma band activity by absolute prediction errors. This is in contrast to prediction errors in visual and auditory perception, which are associated with increased gamma band activity, but is in agreement with observations in working memory and word matching, which show gamma band activity for correct, rather than violated predictions.

neuroscience↗

bioRxiv2020

Twist regulates Yorkie to guide lineage reprogramming of syncytial alary muscles

The genesis of syncytial muscles is typically considered as a paradigm for an irreversible developmental process. Notably, transdifferentiation of syncytial muscles is naturally occurring during Drosophila development. The ventral longitudinal heart-associated musculature (VLM) arises by a unique mechanism that revokes the differentiated fate from the so-called alary muscles and comprises at least two distinct steps: syncytial muscle cell fragmentation into single myoblasts and direct reprogramming into founder cells of the VLM lineage. Here we provide evidence that the mesodermal master regulator twist plays a key role during this reprogramming process. Acting downstream of Drosophila Tbx1 (Org-1) in the alary muscle lineage, Twist is crucially required for the derepression of the Hippo pathway effector Yki and thus for the initiation of syncytial muscle dedifferentiation and fragmentation. Subsequently, cell-autonomous FGFR-Ras-MAPK signaling in the resulting mono-nucleated myoblasts is maintaining Twist expression, thereby stabilizing nuclear Yki activity and inducing their lineage switch into the founder cells of the VLM.

developmental biology↗

bioRxiv2020

TMEM70 promotes ATP synthase assembly within cristae via transient interactions with subunit c

Mitochondrial ATP-synthesis is catalyzed by a F1Fo-ATP synthase, an enzyme of dual genetic origin enriched at the edge of cristae where it plays a key role in their structure/stability. The enzymes biogenesis remains poorly understood, both from a mechanistic and a compartmentalization point of view. The present study provides novel molecular insights into this process through investigations on a human protein called TMEM70 with an unclear role in the assembly of ATP synthase. A recent study has revealed the existence of physical interactions between TMEM70 and the subunit c (Su.c), a protein present in 8 identical copies forming a transmembrane oligomeric ring (c-ring) within the ATP synthase proton translocating domain (FO). Herein we analyzed the ATP-synthase assembly in cells lacking TMEM70, mitochondrial DNA or F1 subunits and observe a reciprocal dependence of TMEM70 and Su.c levels, regardless of the status of other ATP synthase subunits or of mitochondrial bioenergetics. Immunoprecipitation and two-dimensional blue-native/SDS-PAGE reveal that TMEM70 forms large oligomers composed of 8 TMEM70 dimers and that TMEM70 oligomers interact with Su.c not yet incorporated into ATP synthase complexes. Moreover, discrete TMEM70-Su.c complexes with increasing Su.c contents can be detected, suggesting a role for TMEM70 oligomers in the gradual assembly of the c-ring. Furthermore, we demonstrate using expansion super-resolution microscopy the specific localization of TMEM70 at the inner cristae membrane, distinct from the MICOS component MIC60. Taken together, our results show that TMEM70 oligomers provide a scaffold for c-ring assembly and that mammalian ATP synthase is assembled within inner cristae membranes.

cell biology↗

bioRxiv2019

Stem cell-derived cranial and spinal motor neurons reveal proteostatic differences between ALS resistant and sensitive motor neurons

In amyotrophic lateral sclerosis (ALS) spinal motor neurons (SpMN) progressively degenerate while a subset of cranial motor neurons (CrMN) are spared until late stages of the disease. Using a rapid and efficient protocol to differentiate mouse embryonic stem cells (ESC) to SpMNs and CrMNs, we now report that ESC-derived CrMNs accumulate less human (h)SOD1 and insoluble p62 than SpMNs over time. ESC-derived CrMNs have higher proteasome activity to degrade misfolded proteins and are intrinsically more resistant to chemically-induced proteostatic stress than SpMNs. Chemical and genetic activation of the proteasome rescues SpMN sensitivity to proteostatic stress. In agreement, the hSOD1 G93A mouse model reveals that ALS-resistant CrMNs accumulate less insoluble hSOD1 and p62-containing inclusions than SpMNs. Primary-derived ALS-resistant CrMNs are also more resistant than SpMNs to proteostatic stress. Thus, an ESC-based platform has identified a superior capacity to maintain a healthy proteome as a possible mechanism to resist ALS-induced neurodegeneration.

neuroscience↗