Biology subjects

Rezeli, M.

Publications and source records attributed to Rezeli, M..

8 recordsLinked to original sources

bioRxiv2026

A convergent metabolic-kinase signaling axis links Parkinson s disease and multiple system atrophy

Parkinsons disease (PD) and multiple system atrophy (MSA) are alpha-synucleinopathies with overlapping clinical phenotypes but distinct cellular pathological hallmarks. Whether these disorders share upstream molecular changes beyond alpha-synuclein aggregation remains unresolved. Here, we generated induced pluripotent stem cell (iPSC)-derived midbrain spheroids containing dopaminergic neurons from individuals with monogenic PD, idiopathic PD, MSA, and controls, and applied integrated proteomics, metabolomics, and phosphoproteomics to define disease-associated biochemical programs and their regulatory architecture. Despite their distinct etiologies, PD and MSA spheroids displayed highly concordant molecular remodeling, with cellular metabolism emerging as the dominant shared disturbance. Network analyses identified coordinated changes in central carbon metabolism, oxidative phosphorylation, branched-chain amino acid catabolism, pantothenate/CoA metabolism, and lipid remodeling, coupled to phosphorylation-driven rewiring of MAPK, mTOR, AMPK, PKA/PKC, and second-messenger kinase programs. Importantly, these metabolic and signaling axes were also prominent in postmortem substantia nigra from PD and MSA donors, supporting conservation between patient-derived models and postmortem brain tissue. Together, these data identify metabolic dysregulation as a unifying molecular feature across PD and MSA and suggesting phosphorylation-linked metabolic control nodes as candidate entry points for therapeutic intervention. HighlightsO_LIPD and MSA exhibit molecular programs that extend beyond alpha-synuclein pathology. C_LIO_LIProteomics identifies metabolism as the dominant shared disease axis across PD and MSA. C_LIO_LIMetabolomics resolves a coupled glucose-TCA-BCAA-CoA-lipid remodeling program in PD and MSA. C_LIO_LIPhosphorylation-centered kinase networks link signaling rewiring to metabolic bottlenecks. C_LIO_LIShared metabolic features are conserved between patient iPSC-derived midbrain spheroids and substantia nigra. C_LI Graphic abstract (generated using BioRender) O_FIG O_LINKSMALLFIG WIDTH=191 HEIGHT=200 SRC="FIGDIR/small/731777v1_ufig1.gif" ALT="Figure 1"> View larger version (77K): org.highwire.dtl.DTLVardef@1748e51org.highwire.dtl.DTLVardef@12b8f91org.highwire.dtl.DTLVardef@de8893org.highwire.dtl.DTLVardef@1d89ea1_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Phosphoproteomic profiling reveals post-translational dysregulation in Huntington's disease patient-derived neurons

Huntingtons disease (HD) is a fatal neurodegenerative disorder caused by a CAG repeat expansion in the Huntingtin (HTT) gene. Although transcriptomic and proteomic changes have been characterized in patient-derived neurons, the contribution of post-translational modifications (PTMs), such as phosphorylation, remains poorly understood. Here, we present the first phosphoproteomic analysis by mass spectrometry (P-MS) of human induced neurons (iNs) directly reprogrammed from HD patient fibroblasts. We identified 177 phosphopeptides with significantly altered abundance in HD-iNs, mapping to phosphoproteins associated with key signaling pathways known to be affected in HD, such as splicing and autophagy. By integrating P-MS data with previously published proteomic and transcriptomic data from the same donors, we identified distinct subsets of ON-OFF phosphopeptides that exhibited a complete loss of phosphorylation in either HD- or Ctrl-iNs, without corresponding changes at the RNA or protein level. An exception was MXRA8, previously described in glial cells as a mediator of blood-brain barrier integrity and astrocyte-mediated neuroinflammation. This protein showed increased protein abundance despite the absence of phosphorylation in HD- iNs, suggesting a compensatory mechanism - a pattern also observed in human post mortem cortical HD tissue. Additionally, MXRA8 showed altered protein-protein interactions with lysosomal and metabolic regulators in HD-iNs, highlighting its potential role in autophagy impairment as well as in neurovascular dysfunction. These findings uncover a distinct layer of post-translational dysregulation in HD, suggesting that phospho-switch proteins such as MXRA8 may be candidate effectors of pathology and thus site-specific phosphorylation loss may contribute to impaired signaling and proteostasis in human HD neurons.

neuroscience↗

bioRxiv2023

Histopathology-assisted proteogenomics provides foundations for stratification of melanoma metastases

Here we describe the histopathology-driven proteogenomic landscape of 142 treatment-naive metastatic melanoma samples. We identified five proteomic subtypes that integrate the immune and stroma microenvironment components, and associate with clinical and histopathological parameters, providing foundations for an in-depth molecular classification of melanoma. Our study shows that BRAF V600 mutated melanomas display heterogeneous biology, where the presence of an oncogene-induced senescence-like phenotype improves patient survival. Therefore, we propose a mortality-risk-based stratification, which may contribute to a more personalized approach to patient treatment. We also found a strong association between tumor microenvironment composition, disease progression, and patient outcome supported by single-cell omic signatures that point to straightforward histopathological connective tissue-to-tumor ratio assessment for better informed medical decisions. A melanoma-associated signature of single amino acid variants (SAAV) responsible for remodeling the extracellular matrix was uncovered together with SAAV-derived neoantigen candidates as targets of anti-tumor immune responses. Overall, this study offers comprehensive stratifications of melanoma metastases that may help develop tailored strategies for diagnosing and treating the disease.

cancer biology↗

bioRxiv2023

Proteomic analysis across patient iPSC-based models and human post-mortem hippocampal tissue reveals early cellular dysfunction, progression, and prion-like spread of Alzheimer s disease pathogenesis

The hippocampus is a primary region affected in Alzheimers disease (AD). Because AD postmortem brain tissue is not available prior to symptomatic stage, we lack understanding of early cellular pathogenic mechanisms. To address this issue, we examined the cellular origin and progression of AD pathogenesis in patient-based model systems including iPSC-derived brain cells transplanted into the mouse brain hippocampus. Notably, proteomic analysis of the graft enabled the identification of proteomic alterations in AD patient brain cells, associated with increased levels of {beta}-sheet structures and A{beta}42 peptides. Interestingly, the host cells surrounding the AD graft also presented alterations in cellular biological pathways. Furthermore, proteomic analysis across human iPSC-based models and human post-mortem hippocampal tissue projected coherent longitudinal cellular changes indicative of disease progression from early to end stage AD. Our data showcase patient-based models to study the cellular origin, progression, and prion-like spread of AD pathogenesis. Highlights- AD patient iPSC-derived brain cells survive in the hippocampus of immunodeficient mice 6 months post-transplantation. - Proteomic analysis of the grafts reveals profound alterations in cellular biological pathways in iPSC-derived hippocampal cells despite absence of senile plaques. - Proteomic alterations within transplanted AD iPSC-derived hippocampal cells are reminiscent of early/prodromal AD. - AD-grafted cells induce proteomic changes in host mouse cells.

neuroscience↗

bioRxiv2022

Proteogenomic Characterization Reveals Therapeutic Opportunities Related to Mitochondrial Function in Melanoma

The dynamics of more than 1900 mitochondrial proteins was explored through quantitative proteomics in 151 melanoma-related tissue samples of both surgical and autopsy origin. Dysregulation of mitochondrial pathways in primary tumors, metastases, and peritumoral tissues was correlated with age and survival of patients, as well as with tumor cell proliferation and the BRAF mutation status of the tumors. The outlined proteomic landscape confirmed the central role of a pathologically upregulated mitochondrial translation machinery and oxidative phosphorylation (OXPHOS) in the development, proliferation, and progression of melanomas. Our results from different melanoma cell lines confirmed our findings and we could document that treatments with selected OXPHOS inhibitors and antibiotics successfully impaired tumor cell proliferation. In addition, we provided proteomic evidence on the mechanism-of-action of the different treatments. These observations could contribute to the development of therapeutic approaches targeting the mitochondrial pathology in melanoma. TOC figure O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=134 SRC="FIGDIR/small/513481v1_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@11f21e2org.highwire.dtl.DTLVardef@e98c64org.highwire.dtl.DTLVardef@100145forg.highwire.dtl.DTLVardef@399284_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIMitochondrial proteome landscape outlined in 151 melanoma-related samples C_LIO_LIMitochondrial Translation and OXPHOS impact disease severity and survival C_LIO_LIBRAF V600E mutation correlates with upregulation of mitochondrial energy production C_LIO_LITargeting the mitochondrial OXPHOS and ribosomes impairs tumor cell proliferation C_LIO_LITherapeutic opportunities complementary to the standard of care are proposed C_LI In briefMitochondrial proteome profiling of melanomas reveals dysregulation in major metabolic pathways, suggesting a central role of the mitochondria within the development and progression of melanoma. Targeting mitochondrial pathways has the potential to impact the course of the disease, which provides opportunities for complementary drug interventions.

cancer biology↗

bioRxiv2021

Proteogenomics Reveals how Metastatic Melanoma Modulates the Immune System to Allow Immune Evasion

Malignant melanoma (MM) develops from the melanocytes and in its advanced stage is the most aggressive type of skin cancer. Here we report a comprehensive analysis on a prospective cohort study, including non-tumor, primary and metastasis tissues (n=77) with the corresponding plasma samples (n=56) from patients with malignant melanoma. The tumors and surrounding tissues were characterized with a combination of high-throughput analyses including quantitative proteomics, phosphoproteomics, acetylomics, and whole exome sequencing (WES) combined with in-depth histopathology analysis. Melanoma cell proliferation highly correlates with dysregulation at the proteome, at the posttranslational- and at the transcriptome level. Some of the changes were also verified in the plasma proteome. The metabolic reprogramming in melanoma includes upregulation of the glycolysis and the oxidative phosphorylation, and an increase in glutamine consumption, while downregulated proteins involved in the degradation of amino acids, fatty acids, and the extracellular matrix (ECM) receptor interaction. The pathways most dysregulated in MM including the MAP kinases-, the PI3K-AKT signaling, and the calcium homeostasis, are among the most affected by mutations, thus, dysregulation in these pathways can be manifested as drivers in melanoma development and progression. The phosphoproteome analysis combined with target-based prediction mapped 75% of the human kinome. Melanoma cell proliferation was driven by two key factors: i) metabolic reprogramming leading to upregulation of the glycolysis and oxidative phosphorylation, supported by HIF-1 signaling pathway and mitochondrial translation; and ii) a dysregulation of the immune system response, which was mirrored by immune system processes in the plasma proteome. Regulation of the melanoma acetylome and expression of deacetylase enzymes discriminated between groups based on tissue origin and proliferation, indicating a way to guide the successful use of HDAC inhibitors in melanoma. The disease progression toward metastasis is driven by the downregulation of the immune system response, including MHC class I and II, which allows tumors to evade immune surveillance. Altogether, new evidence is provided at different molecular levels to allow improved understanding of the melanoma progression, ultimately contributing to better treatment strategies. TOC figure O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=157 SRC="FIGDIR/small/439245v1_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@937db9org.highwire.dtl.DTLVardef@1230b57org.highwire.dtl.DTLVardef@1bd889eorg.highwire.dtl.DTLVardef@547d90_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2021

Distinct sub-cellular autophagy impairments occur independently of protein aggregation in induced neurons from patients with Huntington's disease

Huntingtons disease (HD) is a neurodegenerative disorder caused by CAG expansions in the huntingtin (HTT) gene. Modelling HD has remained challenging, as rodent and cellular models poorly recapitulate the disease. To address this, we generated induced neurons (iNs) through direct reprogramming of human skin fibroblasts, which retain age-dependent epigenetic characteristics. HD-iNs displayed profound deficits in autophagy, characterised by reduced transport of late autophagic structures from the neurites to the soma. The neurite-specific alterations in autophagy resulted in shorter, thinner and fewer neurites presented by HD-iNs. CRISPRi-mediated silencing of HTT did not rescue this phenotype but rather resulted in additional autophagy alterations in ctrl-iNs, highlighting the importance of wild type HTT in neuronal autophagy. In summary, our work identifies a distinct subcellular autophagy impairment in aged patient derived HD-neurons and provides a new rational for future development of autophagy activation therapies.

neuroscience↗

bioRxiv2019

Post-transcriptional mechanisms distinguish human and chimp forebrain progenitor cells

The forebrain has expanded in size and complexity during hominoid evolution. The contribution of post-transcriptional control of gene expression to this process is unclear. Using in-depth proteomics in combination with bulk and single-cell RNA sequencing, we analyzed protein and RNA levels of almost 5,000 genes in human and chimpanzee forebrain neural progenitor cells. We found that species differences in protein expression level was often independent of RNA levels, and more frequent than transcriptomic differences. Low-abundant proteins were more likely to show species-specific expression levels, while proteins expressed at a high level appeared to have evolved under stricter constraints. Our study implicates a previously unappreciated broad and important role for post-transcriptional regulatory mechanisms in the evolution of the human forebrain.

neuroscience↗