Biology subjects

Berger, A.

Publications and source records attributed to Berger, A..

At least 19 recordsLinked to original sources

bioRxiv2026

Modeling lung adenocarcinoma using layer-by-layer nanoparticles mitigates innate immune cell activation

Lung adenocarcinoma, driven frequently by KRAS and p53 mutations, remains a leading cause of cancer mortality. Current state-of-the-art genetically engineered mouse models often rely on viral delivery of recombinases, such as Cre recombinase, to initiate transformation. However, viral particles can infect and activate innate immune cells, thus potentially impacting studies of tumor-immune dynamics. Here, we develop a layer-by-layer (LbL) polyplex platform using poly({beta}-aminoester) (PBAE) polymers layered with poly-L-aspartic acid (PLD) to deliver Cre mRNA to lungs while avoiding immune cell transfection and activation. PLD-coated nanoparticles (PLD-NPs) exhibit stable mRNA encapsulation and efficient transfection in vitro, even after lyophilization and long-term storage. In KrasLSL-G12D/+;p53flox/flox (KP) mice, PLD-NPs initiate lung adenocarcinomas that mirror human histopathology without infecting or activating dendritic cells and alveolar macrophages, unlike lentiviral (LV) or adenoviral delivery methods. Single-cell transcriptional profiling revealed that LV administration drives long-term upregulation of antigen presentation and costimulatory machinery in lung-resident myeloid populations. This persistent immune activation is avoided by NP delivery. By uncoupling tumor initiation from innate immune activation, this platform enables the high-fidelity interrogation of tumor-immune dynamics, especially for non-inflammation-driven lung cancer.

immunology↗

bioRxiv2026

Why woodiness repeatedly evolves--and disappears

Derived woodiness--the evolution of woody growth from herbaceous ancestors--has arisen hundreds of times across flowering plants, yet the environmental conditions associated with its repeated evolution remain poorly understood. Here, we analyse woodiness evolution in the mustard family (Brassicaceae; ~4,150 species) using a time-calibrated phylogeny of 2,927 species, including 374 of the 385 known woody species, together with global growth-form and climatic niche data. We infer 231 independent origins of woodiness alongside 176 reversals to herbaceousness, indicating that woodiness evolves repeatedly but remains evolutionarily unstable. Although woody species are enriched on islands, most occur on the mainland, where woodiness is consistently associated with drought and reduced frost. Correlated-evolution analyses reveal that drought is associated primarily with the persistence of woodiness, whereas reduced frost is associated with gains of woodiness and increased frost with its loss. These findings identify distinct climatic associations with the gain, persistence, and loss of woody growth forms.

evolutionary biology↗

bioRxiv2026

In vivo modulation of locus coeruleus activity by light

Dysfunction of the Locus coeruleus (LC), a small brainstem nucleus which consists of the brains primary source of norepinephrine, is linked to various neurological and psychiatric disorders. Light exposure influences many non-image-forming (NIF) biological functions including those modulated by LC activity. Yet direct evidence of light-driven modulation of the LC has remained elusive due to the structures small size and deep location. Using ultra-high-field (7 Tesla) functional MRI during an emotional task under varying illuminances, we demonstrate that light modulates LC activity in an emotion-dependent manner. We show that increased illuminance dampens LC responses to negative emotional stimuli while enhancing responses to neutral stimuli. Furthermore, we provide tentative evidence that within an emotional context, light may affect LC activity through the basomedial nucleus of the amygdala as well as through a region of the hypothalamus encompassing the lateral hypothalamus. These findings open avenues for the development of targeted, non-pharmacological treatments leveraging light to modulate norepinephrine tone and/or LC activity in several neuropsychiatric disorders. Significance StatementDysfunction of the Locus Coeruleus (LC), a small nucleus of brain and the main source of norepinephrine, is linked to various brain disorders. Here we provide in vivo evidence that exposure to light can alter the activity of the LC with higher illuminance leading to dampened LC responses to negative emotional stimuli. These findings identify the LC as a key target for the therapeutic effects of light on emotion, offering a biological framework for using light to treat neuropsychiatric disorders.

neuroscience↗

bioRxiv2026

Beyond Histology: A Unified Transcriptomic Atlas Defines Lung Cancer Biologic States and Subtypes

Lung cancer encompasses multiple histological entities with substantial molecular heterogeneity that remain incompletely resolved at population scale. Here, we constructed a unified reference landscape of lung cancer by analyzing raw RNA sequencing data from 1,824 tumors spanning adenocarcinoma (n=966), squamous cell carcinoma (n=628), small cell lung cancer (n=150), and unclassified non small cell lung cancer (n=80). Following batch correction, samples were analyzed using consensus clustering and visualized with PaCMAP to generate a molecular atlas annotated with clinical and biological metadata. Rather than segregating by pathological diagnosis, tumors organized along conserved transcriptional axes defined by tumor-intrinsic biology including proliferative or metabolic programs and immune-infiltrated states. Consensus clustering resolved nine robust molecular clusters, including an adenocarcinoma-associated subgroup, a neuroendocrine-like adenocarcinoma marked by ASCL1 activation, immune-associated regions, and bifurcation of both small cell and squamous carcinomas into biologically distinct states. Spatially restricted expression of selected clinically relevant transcripts nominated state-specific therapeutic hypotheses requiring future functional and clinical validation. Projection of patient tumors and patient-derived xenografts onto the atlas demonstrated preservation of transcriptional identity and enabled quantitative assessment of model fidelity. This integrated framework organizes lung cancer as a structured continuum of transcriptional states and provides a reference resource for biological interpretation and future translational studies.

bioinformatics↗

bioRxiv2026

ViroSeek: a viral detection pipeline for second-generation sequencing

Arbovirus emergences represent a rising public health issue and are exacerbated by climate change and globalization. Virome analysis has become a key approach for monitoring and managing infectious diseases, yet existing tools often remain technically complex and inaccessible to non-specialists. In this context, we present ViroSeek, a reproducible and accessible bioinformatics pipeline specifically designed for the taxonomic analysis of second-generation sequencing data from target-enriched libraries. ViroSeek performs a series of automated steps: quality control, trimming, host and bacterial sequence removal, assembly, taxonomic assignment, read remapping for quantification, and PCR duplicate removal. The whole process is designed to produce a clear, usable viral taxonomy table that is suitable for diversity studies. ViroSeek was empirically validated on enriched control samples containing a known panel of viruses. All the expected viruses were correctly detected. Bacterial and host contaminant sequences were effectively removed. The pipeline is freely available and fully documented, supporting its adoption and adaptation by the research community.

bioinformatics↗

bioRxiv2025

Culex (Culex) acharistus, Root, 1927 (Diptera: Culicidae), a new record for Bolivia

This study reports the first confirmed records of Culex (Culex) acharistus, Root, 1927 in Bolivia, based on both morphological examination and biomolecular identification using the cytochrome c oxidase subunit I (COI) marker. Specimens were collected in four localities representing diverse environmental settings: La Paz (urban environment, {asymp}3600 m), the nearby high-altitude city of El Alto ({asymp}4000 m), Cochabamba (semi-rural and urban habitats, {asymp}2600 m), and Licoma a large village in the Yungas region (subtropical environment, {asymp}1900 m). The larval habitats where the species was found closely match those reported in neighboring countries where Cx. acharistus also occurs, ranging from typical small peridomestic sites to ponds, ditches, and river seepages in semi-rural areas. All identification methods yielded unambiguous results, confirming the species presence in Bolivia and extending its known distribution in South America. This finding highlights the importance of integrating morphological and molecular approaches to achieve accurate and reliable mosquito species identification.

ecology↗

bioRxiv2025

Up-to-date MALDI-TOF MS based identification of the complete Corynebacterium diphtheriae species complex for improved diagnostics

The Corynebacterium (C.) diphtheriae species complex (CdSC) comprises the closely related pathogenic species C. diphtheriae, C. belfantii, C. rouxii, C. ulcerans, C. silvaticum, C. ramonii and C. pseudotuberculosis according to the taxonomic revisions after 2018. Due to their close relationship, reliable species identification within the CdSC is also challenging using MALDI-TOF mass spectrometry (MS) for fast and reliable identification of bacteria. However, the most commonly used commercial databases for MALDI-TOF MS do not reflect the current CdSC taxonomy. Therefore, the objective of the present study is to expand the Bruker MALDI-Biotyper database version K (MBTK) in order to achieve reliable identification for all currently known Corynebacterium species within the CdSC. Furthermore, the database extensions were verified with a systematic formal validation procedure in accordance with the German guideline for species identification by MALDI- TOF MS. For this, 321 strains including all seven valid species of the CdSC were identified with a set of 328 spectra using the commercial MBTK database and a customer-supplemented modified MBTK. This custom database version included 33 reference spectra of the CdSC and representatives of all four recently described species. The results of the formal validations for both, the commercial and the extended database, combined partly with a single signal analysis, provide a substantiated basis for the identification of bacteria of the CdSC. A key element for a fast up-to-date identification has been the exchange of user-generated sets of MSPs on the open access MALDI-UP catalogue that includes reference spectra for all members of the CdSC. HighlightsO_LIUsing MALDI-TOF MS, all current species of the C. diphtheriae species complex are accurately identified according to the current taxonomy C_LIO_LIValidation was performed using spectra from different institutions and an approved gold standard protocol C_LIO_LIThe extension and exchange of user created reference spectra via the MALDI User Platform proved to be a key tool for precise identification of bacteria C_LI Importance StatementBacteria belonging to the Corynebacterium (C.) diphtheriae complex are important pathogens for humans and animals. Identification of the species of this complex described since 2018, i.e. C. belfantii, C. rouxii, C. ramonii, and C. silvaticum, using the widely approved MALDI-TOF mass spectrometry is possible. This has been achieved by improved identification using supplemented MALDI reference databases. Comprehensive validation meets the requirements for accurate pathogen identification in accordance with recognised guidelines. This approach of identification is certainly a model for other bacterial species of interest to react on current taxonomic revisions in a short time frame.

microbiology↗

bioRxiv2025

Factors Influencing Phenomic Prediction: A Case Study on a Large Sorghum BCNAM Population

Plant breeding efficiency is crucial to develop varieties able to cope with climate change and support food and feed value chains. Genomic prediction (GP) has been a major step in increasing this efficiency and is now routinely used in breeding programs. Recently, phenomic prediction (PP) has gained attention as a promising complementary approach to GP, further increasing the breeding programs efficiency. Factors impacting the predictive ability (PA) of PP have been studied on many species but are not fully clarified. In this context, we studied the impacts of spectra pre-processing, prediction methods, population structure, training set size, NIRS acquisition environment and wavelength selection on a large multi-parental sorghum population including 2498 genotypes. Our results show that PP can compete with GP, that it is less affected by population structure, and can reach its maximal PA with smaller training sets than GP, but its performances are trait dependant. We also show that NIRS can be acquired in a reference environment to perform prediction in other environments and that it is possible to randomly select as little as 10 wavelengths to perform predictions. Finally, we show that spectra pre-processing, and statistical methods have a limited and unclear impact on PA. Our study confirms that PP is a relevant trait prediction method that deserves attention to optimize breeding schemes. The main challenges for the future will be to better understand the information contained in the spectra and disentangle their genetic and proxy components to optimize the use of PP in breeding programs. Key messagePhenomic prediction is promising for sorghum breeding. Geneticists methods may not be suited to optimally extract spectral information.

genomics↗

bioRxiv2024

Mutant RIT1 cooperates with YAP to drive an EMT-like lung cancer state

The discovery of oncogene addiction in cancer has led to the development of over a dozen FDA-approved biomarker-driven therapies in lung adenocarcinoma. Somatic mutations of the "Ras-like in all tissues" (RIT1) gene are non-canonical driver events in lung cancer, occurring in [~]2% of lung adenocarcinomas in a mutually exclusive fashion with KRAS and EGFR mutations. Patients with RIT1-mutant lung cancer lack targeted therapy treatment options, and a lack of pre-clinical models has hindered the development of therapeutic strategies for RIT1-mutant lung cancer. Here we report a new mouse model of RIT1-driven lung cancer in which the human RIT1M90I variant can be induced in a Cre-regulated manner. We show that autochthonous expression of RIT1M90I in the lung weakly promotes cancer alone or in combination with loss of the p53 tumor suppressor. However, potent synergy between RIT1M90I and inactivation of Nf2 drives an aggressive epithelial-to-mesenchymal (EMT) lung cancer with 100% penetrance and short latency. We show this oncogenic cooperation is driven by synergistic activation of cJUN, a component of the AP-1 complex. Therapeutic inhibition of MEK and YAP/TEAD suppressed RIT1-driven lung cancer in vivo. These data identify YAP/TEAD as an important mediator of RIT1s oncogenic potential and nominate TEAD as an important drug target in RIT1-mutant lung cancer. HIGHLIGHTSO_LIWe report a new RIT1M90I-mutant autochthonous lung tumor model C_LIO_LIThe most common oncogenic variant of RIT1, RIT1M90I, weakly promotes lung tumor development C_LIO_LIRIT1M90I drives the formation of lethal lung tumors in cooperation with p53 and Nf2 tumor suppressor gene loss C_LIO_LIRIT1M90I and YAP cooperatively regulate cJUN expression C_LIO_LITherapeutic MEK and TEAD targeting suppresses RIT1M90I-driven tumorigenesis C_LI

cancer biology↗

bioRxiv2024

Genetic modulation of yield and phenotypic plasticity of yield in winter wheat

For winter wheat in the US Central Great Plains, phenotypic plasticity of yield is agronomically adaptive, i.e., genotypes with higher plasticity have higher yield in high yielding environments with no tradeoff in stressful, low yielding environments. Using data from variety trials conducted between 2000 and 2022 and cultivars released between 1967 and 2022, we explored time trends in phenotypic plasticity and heritability of yield. We hypothesize that i) if yield plasticity is agronomically adaptive, then newer cultivars will have higher yield plasticity; ii) heritability of yield is declining in the time series; and iii) genomic regions associated with yield depend on the environment and do not fully overlap with those associated with phenotypic plasticity of yield. Breeding for yield and agronomic adaptation increased phenotypic plasticity of yield at 0.5% year -1; broad sense heritability of yield decreased from 0.23 in 1993 to 0.15 in 2017. Genome-wide-association analysis shows genomic regions associated with yield varied between high yielding and stressful environments and were partially independent of those associated with yield plasticity. Newer cultivars have a higher frequency of alleles associated with yield and its plasticity. We discuss implications for breeding and agronomy aimed to improve wheat phenotypes.

genetics↗

bioRxiv2024

Cellular processing of beneficial de novo emerging proteins

Recent evidence demonstrates that eukaryotic genomes encode thousands of evolutionarily novel proteins that originate de novo from non-coding DNA and can contribute to species-specific adaptations. Yet, it remains unclear how these incipient proteins--whose sequences are entirely new to nature--navigate the cellular environment to bring about phenotypic change. Here, we conduct a systematic in vivo investigation of yeast de novo proteins with enhanced growth phenotypes, revealing the early stages of cellular integration. We find that these proteins are strongly enriched at the endoplasmic reticulum (ER) relative to conserved proteins, and that they integrate into cellular systems through conserved membrane targeting, trafficking, and degradation pathways. Despite having unrelated sequences, ER-localized de novo proteins share a common molecular signature: a C-terminal transmembrane domain that likely enables recognition by conserved post-translational ER insertion pathways. After insertion, ER-localized de novo proteins traffic from the ER and their homeostasis is regulated by conserved proteasomal and vacuolar degradation pathways. Our findings demonstrate that ancient targeting and degradation pathways can accommodate young de novo proteins sharing a convergent molecular signature. These pathways may act as selective filters, biasing which young de novo proteins persist. Significance StatementDeeply conserved genes shape the core structure and function of cells, but novel genes are key drivers of biodiversity. Novel genes can arise by divergence from ancient genes, or de novo from non-genic DNA. For de novo genes to develop novel functions, it is necessary for them to be processed by the cell so that their protein levels and localization are regulated. However, little is known about how novel de novo genes obtain the capacity to engage the cellular machinery needed for this regulation. Here, we experimentally assess how a set of endoplasmic reticulum (ER)-localized proteins encoded by recently-evolved de novo genes are localized and degraded in yeast cells. We discover that, despite having entirely unique amino acid sequences, these proteins share biochemical signatures allowing them to engage the same ancient cellular machinery and localize to the ER membrane. Interestingly though, this machinery is not the one that targets most ancient proteins to the ER. These results indicate that even recently emerged proteins without an extensive period of evolutionary adaptation can be recognized by specific ancient cellular pathways, facilitating their localization and homeostasis.

evolutionary biology↗

bioRxiv2024

Using nature-based citizen science initiatives to enhance nature connection and mental health.

The global rise in mental health issues underscores the critical importance of assessing the mental health benefits of engaging with nature. Beyond their primary aim of involving citizens in scientific data collection, nature-based citizen science initiatives offer significant potential for enhancing conservation (e.g. connection to nature) and human health and wellbeing (e.g. emotions, depression, stress, anxiety) outcomes. However, the effectiveness of various types of initiatives in achieving specific health outcomes remain unclear. This study evaluates changes in eight nature connection and health and wellbeing outcomes before and after participation in five such initiatives, specifically three dimensions of connection to nature (Self, Experience and Perspective) measured by the Nature Relatedness scale), and mental health outcomes--depression, stress and anxiety--measured by the DASS-21 scale; along with positive and negative emotions assessed using the Scale of Positive and Negative Experience (SPANE). We found that participants generally reported improvements across all outcomes, but only positive emotions and reduced anxiety and stress symptoms were significantly enhanced. This suggests that short-term nature-based interventions are effective in boosting emotions and alleviating anxiety and stress, though significant changes in nature connection and depression may require prolonged or more intensive engagement. We also found that the Queensland Trust for Nature initiative, characterized by its extended duration and social interactions, emerged as a particularly effective model in achieving synergies between biodiversity and human health goals. Consequently, we advocate for the reimagining of these nature-based initiatives as integral components of broader health-promoting strategies. By aligning citizen science efforts with health promotion frameworks, we can amplify the utility and impact of nature-based citizen science initiatives, enhancing their contributions to scientific knowledge, nature conservation and human health.

ecology↗

bioRxiv2024

REM sleep quality is associated with balanced tonic activity of the locus coeruleus during wakefulness

BackgroundAnimal studies established that the locus coeruleus (LC) plays important roles in sleep and wakefulness regulation. Whether it contributes to sleep variability in humans is not yet established. Here, we investigated if the in vivo activity of the LC is related to the variability in the quality of Rapid Eye Movement (REM) sleep. MethodsWe assessed the LC activity of 34 healthy younger ([~]22y) and 18 older ([~]61y) individuals engaged in bottom-up and top-down cognitive tasks using 7-Tesla functional Magnetic Resonance Imaging (fMRI). We further recorded their sleep electroencephalogram (EEG) to evaluate associations between LC fMRI measures and REM sleep EEG metrics. ResultsTheta oscillation energy during REM sleep was positively associated with LC response in the top-down task. In contrast, REM sleep theta energy was negatively associated with LC activity in older individuals during the bottom-up task. Importantly, sigma oscillations power immediately preceding a REM sleep episode was positively associated with LC activity in the top-down task. ConclusionsLC activity during wakefulness was related to REM sleep intensity and to a transient EEG change preceding REM sleep, a feature causally related to LC activity in animal studies. The associations depend on the cognitive task, suggesting that a balanced level of LC tonic activity during wakefulness is required for optimal expression of REM sleep. The findings may have implications for the high prevalence of sleep complaints reported in aging and for disorders such as insomnia, Alzheimers, and Parkinsons disease, for which the LC may play pivotal roles through sleep.

neuroscience↗

bioRxiv2024

Exposure to light supresses the activity of the medial and superior amygdala during emotional processing

The brain mechanisms through which changes in season and light exposure modulate mood may involve different nuclei of the amygdala. We aimed to test this hypothesis using 7 Tesla functional magnetic resonance imaging in 29 healthy young adults. We first considered time-of-year changes in activity that are related to the slow change in photoperiod. We find that the response to emotional stimuli of selected medial and superior nuclei of the amygdala peaked around the start of winter or increased with worse mood status. We further assessed how alternating short exposures to light of different illuminance acutely affected the regional activity of the amygdala. We show that the same areas showed a linear reduction of activity when exposed to increasing light illuminance, specifically when processing emotional stimuli. Importantly, the impact of light on part of these nuclei peaked around the start of summer or decreased with worse mood. These findings provide new evidence that humans show seasonality and that, for mood, it involves parts of the amygdala. The results bring novel insights into the mechanisms that underlie the long-term and acute impact of light on mood and that may contribute to the benefits of light therapy in the treatment of mood disorders.

neuroscience↗

bioRxiv2024

α-Aminooxyacetic acid derivatives acting as pro-drugs against Mycobacterium tuberculosis

Tuberculosis (TB), a significant cause of mortality globally, continues to claim 1.5 million lives each year. Despite recent advances in TB management, the emergence of multidrug-resistant strains of TB is exacerbating the treatment of TB. Therefore, there is an immediate necessity to uncover new anti-TB compounds with unprecedented targets. This study introduces novel antimycobacterial molecules that are based on -aminooxyacetic acid core structures. The lead compounds KSK-104 and KSK-106 displayed potent sub-micromolar antibacterial activity against Mycobacterium tuberculosis H37Rv and XDR clinical isolates, while exhibiting virtually no cytotoxicity against various human cells. Complementation experiments following whole genome sequencing of spontaneously resistant mutants generated against these bactericidal compounds suggested that they are pro-drugs that are intracellularly hydrolyzed by one or both of two specific amidohydrolases, Rv0552 and AmiC. Furthermore, proteomic and transcriptomic analyses of stressed cells and genetic interaction mapping employing transposon insertion sequencing suggest a "dirty drug" mechanism that involves the simultaneous attack of the various drug cleavage products on multiple intracellular targets. Our results suggest a primary role of the pyridoxal 5-phosphate (PLP) synthesis and salvage pathway and/or PLP-dependent enzymes, the oxidative stress network, and the largely uncharacterized Rv3092c-Rv3095 gene cluster in the mode of action.

microbiology↗

bioRxiv2024

First concrete documentation for presence of Aedes (Stegomyia) albopictus in Bolivia: Dispelling previous anecdotes

BackgroundThe presence of Aedes albopictus in Bolivia has been a subject of controversy, lacking concrete documentation until now. ObjectivesThis study aimed to furnish evidence of Ae. albopictus presence in Bolivia. MethodsLarval breeding sites were sampled in two northern Bolivian localities, Rosario del Yata and San Agustin, both situated in the Beni department within the Vaca Diez province and Guayaramerin Municipio, approximately 10 km apart. Mosquito larvae collected underwent rearing to L4 and adult stages for morphological identification, with some specimens sequenced for confirmation. FindingsAe. albopictus was identified in multiple breeding sites in both localities, confirming its establishment in the area. This marks the first concrete documentation of the species in Bolivia. The collections (larvae and adults) have been deposited in the Medical Entomology Laboratory of the Universidad Mayor de San Simon in Cochabamba, Bolivia, and the Laboratory of Entomology of the Instituto Nacional de Laboratorios de Salud of the Ministry of Health in La Paz, Bolivia. Main conclusionAcknowledging its role as a vector for arboviruses like dengue and Chikungunya, Ae. albopictus should be incorporated into the Bolivian National Program of Vector Control for monitoring.

ecology↗

bioRxiv2024

Microenvironment Shapes Cell State, Plasticity, and Heterogeneity of Small Cell Lung Cancer

Small-cell lung cancer (SCLC) is the most fatal form of lung cancer. Intra-tumoral heterogeneity, marked by neuroendocrine (NE) and non-neuroendocrine (non-NE) cell states, defines SCLC, but the drivers of SCLC plasticity are poorly understood. To map the landscape of SCLC tumor microenvironment (TME), we apply spatially resolved transcriptomics and quantitative mass spectrometry-based proteomics to metastatic SCLC tumors obtained via rapid autopsy. The phenotype and overall composition of non-malignant cells in the tumor microenvironment (TME) exhibits substantial variability, closely mirroring the tumor phenotype, suggesting TME-driven reprogramming of NE cell states. We identify cancer-associated fibroblasts (CAF) as a crucial element of SCLC TME heterogeneity, contributing to immune exclusion, and predicting exceptionally poor prognosis. Together, our work provides a comprehensive map of SCLC tumor and TME ecosystems, emphasizing their pivotal role in SCLCs adaptable nature, opening possibilities for re-programming the intercellular communications that shape SCLC tumor states.

cancer biology↗

bioRxiv2024

Alterations in Lysosomal, Glial and Neurodegenerative Biomarkers in Patients with Sporadic and Genetic Forms of Frontotemporal Dementia

BackgroundFrontotemporal dementia (FTD) is the most common cause of early-onset dementia with 10-20% of cases caused by mutations in one of three genes: GRN, C9orf72, or MAPT. To effectively develop therapeutics for FTD, the identification and characterization of biomarkers to understand disease pathogenesis and evaluate the impact of specific therapeutic strategies on the target biology as well as the underlying disease pathology are essential. Moreover, tracking the longitudinal changes of these biomarkers throughout disease progression is crucial to discern their correlation with clinical manifestations for potential prognostic usage. MethodsWe conducted a comprehensive investigation of biomarkers indicative of lysosomal biology, glial cell activation, synaptic and neuronal health in cerebrospinal fluid (CSF) and plasma from non-carrier controls, sporadic FTD (symptomatic non-carriers) and symptomatic carriers of mutations in GRN, C9orf72, or MAPT, as well as asymptomatic GRN mutation carriers. We also assessed the longitudinal changes of biomarkers in GRN mutation carriers. Furthermore, we examined biomarker levels in disease impacted brain regions including middle temporal gyrus (MTG) and superior frontal gyrus (SFG) and disease-unaffected inferior occipital gyrus (IOG) from sporadic FTD and symptomatic GRN carriers. ResultsWe confirmed glucosylsphingosine (GlcSph), a lysosomal biomarker regulated by progranulin, was elevated in the plasma from GRN mutation carriers, both symptomatic and asymptomatic. GlcSph and other lysosomal biomarkers such as ganglioside GM2 and globoside GB3 were increased in the disease affected SFG and MTG regions from sporadic FTD and symptomatic GRN mutation carriers, but not in the IOG, compared to the same brain regions from controls. The glial biomarkers GFAP in plasma and YKL40 in CSF were elevated in asymptomatic GRN carriers, and all symptomatic groups, except the symptomatic C9orf72 mutation group. YKL40 was also increased in SFG and MTG regions from sporadic FTD and symptomatic GRN mutation carriers. Neuronal injury and degeneration biomarkers NfL in CSF and plasma, and UCHL1 in CSF were elevated in patients with all forms of FTD. Synaptic biomarkers NPTXR, NPTX1/2, and VGF were reduced in CSF from patients with all forms of FTD, with the most pronounced reductions observed in symptomatic MAPT mutation carriers. Furthermore, we demonstrated plasma NfL was significantly positively correlated with disease severity as measured by CDR+NACC FTLD{square}SB in genetic forms of FTD and CSF NPTXR was significantly negatively correlated with CDR+NACC FTLD{square}SB in symptomatic GRN and MAPT mutation carriers. ConclusionsIn conclusion, our comprehensive investigation replicated alterations in biofluid biomarkers indicative of lysosomal function, glial activation, synaptic and neuronal health across sporadic and genetic forms of FTD and unveiled novel insights into the dysregulation of these biomarkers within brain tissues from patients with GRN mutations. The observed correlations between biomarkers and disease severity open promising avenues for prognostic applications and for indicators of drug efficacy in clinical trials. Our data also implicated a complicated relationship between biofluid and tissue biomarker changes and future investigations should delve into the mechanistic underpinnings of these biomarkers, which will serve as a foundation for the development of targeted therapeutics for FTD.

neuroscience↗