Biology subjects

Riessland, M.

Publications and source records attributed to Riessland, M..

8 recordsLinked to original sources

bioRxiv2026

Oxygen-sensing regulatory architecture structures mammalian diversification

The HIF oxygen-sensing pathway traces to the last metazoan common ancestor [~]800 million years ago and is conventionally viewed as a conserved cellular stress-response module. Whether this ancestral system has contributed to mammalian diversification at macroevolutionary timescales remains unexplored. We analyzed sequence-encoded TF-gene regulatory architecture for 34 transcription factors and 705 genes in 10 oxygen-sensing pathways across 239 mammalian species. Oxygen-sensing regulatory architecture carries strong clade-structured evolutionary signal. The primary axis of variation tracks a fast-slow life history gradient, marked by rewiring of growth-control and tumor suppressor hub genes. A second axis recovers the monotreme-marsupial-placental transition and aligns with the decline in atmospheric O2 from the Permo-Carboniferous maximum toward present-day levels1. Orthogonal axes encode distinct ecological regulatory strategies; two later axes separately resolve HIF-compatible binding-site architecture and dominant TF-family assignment, identifying regulatory strategies associated with powered flight and hibernation. This multidimensional space also informs Petos paradox, suggesting that relative cancer resistance tracks the combination of tumor-suppressor enrichment and coordinated HIF-complex assignment. Together, these results indicate that regulatory configurations arise at major evolutionary transitions and persist coherently across descendant lineages through a punctuated mode of regulatory evolution, providing genomic-level evidence for Simpsons adaptive zones and a mechanism for evolutionary stasis. These findings reframe oxygen sensing as a regulatory hub in mammalian diversification, with stable patterns of TF-family assignment configurations emerging as a structuring force in macroevolution. BriefAncient molecular processes such as oxygen-sensing, whose HIF-pathway dates to the origin of animals [~]800 million years ago, are typically regarded as conserved across lineages. How such deeply ancestral systems have contributed to mammalian diversification remains largely unexplored. By analyzing the oxygen-sensing regulatory architecture (which transcription factors regulate which genes) across 239 mammalian species, we find that oxygen-sensing regulatory rewiring tracks placental evolution, atmospheric O2, life history evolution, ecological specializations, and cancer resistance. Major radiations occupy discrete, heritable configurations established at key phylogenetic transitions and subsequently retained across descendant lineages through near-neutral within-regime drift, revealing regulatory architecture lock-in as a structuring force in macroevolution.

evolutionary biology↗

bioRxiv2026

Characterizing the SASP-Dependent Paracrine Spreading of Senescence Between Human Brain Cell Types

One of the defining phenotypes of a senescent cell is the senescence-associated secretory phenotype (SASP), which can propagate senescence in neighboring cells both in vitro and in vivo. Importantly, this paracrine spreading of senescence can act in a cell non-autonomous manner, influencing neighboring cell populations and contributing to immune cell recruitment. As cellular senescence has recently been linked to both age-related neurodegenerative phenotypes and local inflammation and is more clearly defined across brain cell types in a cell-type-dependent manner, an urgent question remains regarding how a cell-type-specific paracrine spreading of senescence occurs in the brain. Here, we set out to profile the cell-type-specific features of the SASP and characterize the directionality of paracrine senescence-spreading between major brain cell types. Through this analysis, we identified key SASP ligand-receptor pairs involved in this paracrine dissemination. Targeting these factors with specific inhibitors, we prevented the paracrine spreading of senescence in a brain cell-type-dependent manner. Taken together, we identified specific SASP targets for therapeutic intervention in the context of human brain cells and thereby informed the SASP-dependent reaction of immune cells and age-related tissue dysfunction across both normal aging and models of neurodegenerative disease.

neuroscience↗

bioRxiv2025

Regulatory Network Inference of Induced Senescent Midbrain Cell Types Reveals Cell Type-Specific Senescence-Associated Transcriptional Regulators

Cellular senescence of brain cell types has become an increasingly important perspective for both aging and neurodegeneration, specifically in the context of Parkinsons Disease (PD). The characterization of classical hallmarks of senescence is a widely debated topic, whereby the context in which a senescence phenotype is being investigated, such as the cell type, the inducing stressor, and/or the model system, is an extremely important aspect to consider when defining a senescent cell. Here, we describe a cell type-specific profile of senescence through the investigation of various canonical senescence markers in five human midbrain cell lines using chronic 5-Bromodeoxyuridine (BrdU) treatment as a model of DNA damage-induced senescence. We used principal component analysis (PCA) and subsequent regulatory network inference to define both unique and common senescence profiles in the cell types investigated, as well as revealed senescence-associated transcriptional regulators (SATRs). Functional characterization of one of the identified regulators, transcription factor AP4 (TFAP4), further highlights the cell type-specificity of the expression of the various senescence hallmarks. Our data indicates that SATRs modulate cell type-specific profiles of induced senescence in key midbrain cell types that play an important role in the context of aging and PD.

neuroscience↗

bioRxiv2025

Nuclear Import Defects Drive Cell Cycle Dysregulation in Neurodegeneration

Neurodegenerative diseases (NDDs) and other age-related disorders have been classically defined by a set of key pathological hallmarks. Two of these hallmarks, cell cycle dysregulation (CCD) and nucleocytoplasmic transport (NCT) defects, have long been debated as being either causal or consequential in the pathology of accelerated aging. Specifically, aberrant cell cycle activation in post-mitotic neurons has been shown to trigger neuronal cell death pathways and cellular senescence. Additionally, NCT has been observed to be progressively dysregulated during aging and in neurodegeneration, where the increased subcellular redistribution of nuclear proteins such as TAR DNA-Binding Protein-43 (TDP43) to the cytoplasm is a primary driver of many NDDs. However, the functional significance of NCT defects as either a primary driver or consequence of pathology, and how the redistribution of cell cycle machinery contributes to neurodegeneration, remains unclear. Here, we describe that pharmacological inhibition of importin-{beta} nuclear import is capable of perturbing cell cycle machinery both in mitotic neuronal cell lines and post-mitotic primary neurons in vitro. Our NemfR86S mouse model of motor neuron disease, characterized by nuclear import defects, further recapitulates the hallmarks of CCD in mitotic cell lines and in post-mitotic primary neurons in vitro, and in spinal motor neurons in vivo. The observed CCD is consistent with the transcriptional and phenotypical dysregulation observed in neuronal cell death and cellular senescence in NDDs. Together, this evidence suggests that impairment of nuclear import pathways resulting in CCD may be a common driver of pathology in neurodegeneration. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=106 SRC="FIGDIR/small/635269v1_figa1.gif" ALT="Figure 1"> View larger version (16K): org.highwire.dtl.DTLVardef@15a17d9org.highwire.dtl.DTLVardef@1d3af6eorg.highwire.dtl.DTLVardef@a291f5org.highwire.dtl.DTLVardef@11c9c5d_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract:C_FLOATNO Overview of Dysregulated Cell Cycle Mechanisms in Neuronal Cells. A nuclear import block drives cell cycle re-entry from G0, culminating in cell cycle arrest at G1/S. This cell cycle arrest is associated with activation of CKIs from the INK locus (p15, p16, p18, p19) and Cip/Kip (p21, p27) which act on specific CDK/Cyclin complexes. This activity is further associated with the G1/S downregulation E2F and stathmins, resulting in microtubule dysregulation and cell cycle arrest. C_FIG

neuroscience↗

bioRxiv2023

The SATB1-MIR22-GBA axis mediates glucocerebroside accumulation inducing a cellular senescence-like phenotype in dopaminergic neurons

Idiopathic Parkinsons Disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, which is associated with neuroinflammation and reactive gliosis. The underlying cause of PD and the concurrent neuroinflammation are not well understood. In this study, we utilized human and murine neuronal lines, stem cell-derived dopaminergic neurons, and mice to demonstrate that three previously identified genetic risk factors for PD, namely SATB1, MIR22HG, and GBA, are components of a single gene regulatory pathway. Our findings indicate that dysregulation of this pathway leads to the upregulation of glucocerebrosides (GluCer), which triggers a cellular senescence-like phenotype in dopaminergic neurons. Specifically, we discovered that downregulation of the transcriptional repressor SATB1 results in the derepression of the microRNA miR-22-3p, leading to decreased GBA expression and subsequent accumulation of GluCer. Furthermore, our results demonstrate that an increase in GluCer alone is sufficient to impair lysosomal and mitochondrial function, thereby inducing cellular senescence dependent on S100A9 and stress factors. Dysregulation of the SATB1-MIR22-GBA pathway, observed in both PD patients and normal aging, leads to lysosomal and mitochondrial dysfunction due to the GluCer accumulation, ultimately resulting in a cellular senescence-like phenotype in dopaminergic neurons. Therefore, our study highlights a novel pathway involving three genetic risk factors for PD and provides a potential mechanism for the senescence-induced neuroinflammation and reactive gliosis observed in both PD and normal aging.

neuroscience↗

bioRxiv2023

TNF-NFkB-p53 axis restricts in vivo survival of hPSC-derived dopamine neuron

Ongoing, first-in-human clinical trials illustrate the feasibility and translational potential of human pluripotent stem cell (hPSC)-based cell therapies in Parkinsons disease (PD). However, a major unresolved challenge in the field is the extensive cell death following transplantation with <10% of grafted dopamine neurons surviving. Here, we performed a pooled CRISPR/Cas9 screen to enhance survival of postmitotic dopamine neurons in vivo. We identified p53-mediated apoptotic cell death as major contributor to dopamine neuron loss and uncovered a causal link of TNFa-NF{kappa}B signaling in limiting cell survival. As a translationally applicable strategy to purify postmitotic dopamine neurons, we performed a cell surface marker screen that enabled purification without the need for genetic reporters. Combining cell sorting with adalimumab pretreatment, a clinically approved and widely used TNFa inhibitor, enabled efficient engraftment of postmitotic dopamine neurons leading to extensive re-innervation and functional recovery in a preclinical PD mouse model. Thus, transient TNFa inhibition presents a clinically relevant strategy to enhance survival and enable engraftment of postmitotic human PSC-derived dopamine neurons in PD. HighlightsO_LIIn vivo CRISPR-Cas9 screen identifies p53 limiting survival of grafted human dopamine neurons. C_LIO_LITNF-NF{kappa}B pathway mediates p53-dependent human dopamine neuron death C_LIO_LICell surface marker screen to enrich human dopamine neurons for translational use. C_LIO_LIFDA approved TNF-alpha inhibitor rescues in vivo dopamine neuron survival with in vivo function. C_LI

neuroscience↗

bioRxiv2018

Loss of SATB1 Induces a p21 Dependent CellularSenescence Phenotype in Dopaminergic Neurons

Cellular senescence is a mechanism used by mitotic cells to prevent uncontrolled cell division. As senescent cells persist in tissues, they cause local inflammation and are harmful to surrounding cells, contributing to aging. Generally, neurodegenerative diseases, such as Parkinson s, are disorders of aging. The contribution of cellular senescence to neurodegeneration is still unclear. SATB1 is a DNA binding protein associated with Parkinsons disease. We report that SATB1 prevents cellular senescence in post-mitotic dopaminergic neurons. Loss of SATB1 causes activation of a cellular senescence transcriptional program in dopamine neurons, both in human stem cell-derived dopaminergic neurons and in mice. We observed phenotypes which are central to cellular senescence in SATB1 knockout dopamine neurons in vitro and in vivo. Moreover, we found that SATB1 directly represses expression of the pro-senescence factor, p21, in dopaminergic neurons. Our data implicate senescence of dopamine neurons as a contributing factor to the pathology of Parkinsons disease.

neuroscience↗

bioRxiv2017

Experience-dependent translational state defined by cell type-specific ribosome profiling

Experience-dependent neuronal activity regulates the translation of mRNA, supporting memory formation. We have developed a new method termed translating ribosome affinity purification and ribosome profiling (TRiP) which allows us to determine cell type-specific ribosome occupancy of mRNA with nucleotide resolution. Using TRiP we show that a memory-inducing experience creates a distinct translational state in mouse CA1 pyramidal cells. The experience-dependent translation state is characterized by enhanced translation of protein-coding open reading frames (ORFs) including numerous components of the actin cytoskeleton and calcium/calmodulin binding proteins, and by decreased translation of a defined subset of genes containing upstream ORFs (uORFs). Using animals heterozygous for an unphosphorylatable allele of the eukaryotic translation initiation factor 2 (eIF2), we show that dephosphorylation of eIF2 contributes significantly to the experience-dependent translation state. These observations demonstrate that TRiP is a valuable methodology for studying physiologically relevant changes in translational state in genetically defined cell types.

genomics↗