Biology subjects

Glerup, S.

Publications and source records attributed to Glerup, S..

7 recordsLinked to original sources

bioRxiv2025

The SorCS2-derived macrocycle TT-P34 drives neuroprotection in animal models of neurodegeneration

Mitochondria are critical for sustaining the high energy demands of neuronal activity and their dysregulation is a hallmark of neurodegeneration. Targeting pathways of neurotrophic signaling is a well-established therapeutic strategy to enhance mitochondrial function and mitigate neurodegeneration. The VPS10p domain receptor, SorCS2, has recently emerged as a receptor with neurotrophic signaling capabilities. Here, we design and develop novel SorCS2-derived macrocyclic peptides mimicking receptor activation in vivo. We show that SorCS2-peptides enhance both neurotrophic support and boost metabolism by activating CREB and AMPK in a CAMKK2-dependent manner. This leads to upregulation of the key transcription factors PGC1 and TFEB and consequentially mitochondrial biogenesis. Furthermore, we show that the lipidated SorCS2 macrocycle, TT-P34, rescues motor behavioral deficits and preserves synaptic and mitochondrial signatures in the zQ175 mouse model of Huntingtons Disease. In addition, treating a MPTP-induced mouse model of Parkinsons Disease leads to amelioration of behavioral deficits and reduction of dopaminergic loss. Finally, we demonstrate that TT-P34 crosses the blood-brain barrier in non-human primates, and estimate human therapeutic dosing by pharmacodynamic modelling. Together, our findings support the use of TT-P34 as a novel disease-modifying therapy targeting SorCS2-receptor signaling to prevent neurodegeneration.

neuroscience↗

bioRxiv2025

Reshaping the progranulin/sortilin interaction for targeted degradation of extracellular proteins

Targeted protein degradation (TPD) using PROteolysis TArgeting Chimeras (PROTACs) is a rapidly emerging therapeutic strategy for difficult-to-drug cytosolic proteins. PROTACs are heterobifunctional small molecules that bridge the target with an E3 ubiquitin ligase, destining it for degradation by the proteasome. They have the potential to be orally available and to act catalytically, switching the pharmacology from occupancy-driven to event-driven (1-3). Here we present a strategy for targeted degradation of extracellular proteins by reshaping the interaction between the broadly expressed lysosome sorting receptor sortilin and its ligand progranulin for engineering SORtilin-based lysosome TArgeting Chimeras (SORTACs). SORTACs induce ternary complex formation with the target and sortilin, followed by endocytosis and lysosomal degradation. SORTAC activity can be genetically encoded as demonstrated by converting an IgG binding nanobody to an IgG degrading nanobody or by chemical conjugation, enabling single step conversion of therapeutic antibodies from binding their target to driving its degradation. Importantly, using structure-based design, we generated small molecule SORTACs against the inflammatory cytokine TNFa with nanomolar range potency and with physicochemical properties like PROTACs. Our results demonstrate that SORTACs constitute a versatile and highly modular platform for rapid generation of degraders of in theory any extracellular target and with the potential to have wide impact in drug discovery.

biochemistry↗

bioRxiv2025

Rare missense variants of the leukocyte common antigen related receptor (LAR) display reduced activity in transcellular adhesion and synapse formation

The leukocyte common antigen related receptor (LAR) is a member of the LAR receptor protein tyrosine phosphatase (RPTP) family of synaptic adhesion molecules that contribute to the proper alignment and specialization of synaptic connections in the mammalian brain. LAR-RPTP members have been genetically associated with neuropsychiatric disorders, but the molecular consequences of genetic perturbations of LAR remain unstudied. Using exome sequencing data from psychiatric patients and controls, we identify rare missense variants of LAR that render the extracellular domain (ECD) unstable and susceptible to proteolytic cleavage. Using recombinant and cellular systems, we describe three variants that cause disruption of the LAR:NGL-3 interaction, which results in loss of transcellular adhesion and synaptogenic effects. Furthermore, we show that overexpression of two of these variants elicit altered morphological phenotypes in an imaging-based morphological profiling assay compared to wild type LAR, suggesting that destabilization of the LAR ECD has broad effects on LAR function. In conclusion, our study identifies three rare, missense variants in LAR that could provide insights into LAR involvement with psychiatric pathobiology.

neuroscience↗

bioRxiv2024

A triple serine motif in the intracellular domains of sortilin-related receptors SorCS1-3 regulates neurotrophic activity

The Vps10p-domain receptors SorCS1-3 have been repeatedly associated with the development of neurological and psychiatric disorders. They have emerged as key regulators of synaptic activity and neurotrophic signaling, but the underlying molecular mechanism remains poorly understood. Here we report that the SorCS1-3 intracellular domains (ICDs) contain a conserved triple serine motif that potentially functions as a signaling switch to induce neurotrophic signaling in hippocampal neurons. We demonstrate that phosphorylation mimicking mutations of the SorCS1-3 triple serine motifs display neurotrophic activity independently of both their extracellular domains (ECDs) and BDNF, and that the substitution of serines to alanines renders neurons less responsive to BDNF. Hence, we develop triple serine motif-based cell-penetrating peptides that modulate downstream signaling kinases of the BDNF pathway, ultimately activating the transcription factor CREB. Taken together, we provide the first mechanistic insights into SorCS1-3 mediated neurotrophic signaling and use this knowledge to develop pharmacologically active modulators.

neuroscience↗

bioRxiv2023

Morphological profiling by cell painting in human neural progenitor cells classifies hit compounds in a pilot drug screen for Alzheimer's disease

1Alzheimers disease (AD) accounts for 60-70% of dementia cases. Current treatments are inadequate and there is a need to develop new approaches to AD drug discovery. We chose to develop a cell phenotype-based drug screen centred on the AD-risk gene, SORL1, which encodes the protein SORLA. Increased AD risk has been repeatedly linked to variants in SORL1, particularly those that confer loss of, or decreased, SORLA. This is consistent with the lower SORL1 levels observed in post-mortem brain samples from individuals with AD. Consistent with its role in the endolysosomal pathway, deletion of SORL1 is associated with enlarged endosomes in neural progenitor cells (NPCs) and neurons. We, therefore, hypothesised that multiparametric, image-based phenotyping would identify features characteristic of SORL1 deletion. An automated morphological profiling assay (known as Cell Painting) was adapted to wild-type and SORL1-/- NPCs. This methodology was used to determine the phenotypic response of SORL1-/- NPCs to treatment with compounds from a small FDA/internationally-approved drug library (TargetMol, 330 compounds). We detected distinct phenotypic signatures for SORL1-/- NPCs compared to isogenic wild-type controls. Furthermore, we identified 16 approved drugs that reversed the mutant morphological signatures in NPCs derived from 3 SORL1-/- subclonal iPSC lines. Network pharmacology analysis revealed the 16 compounds belonged to five mechanistic groups: 20S proteasome, aldehyde dehydrogenase, topoisomerase I and II, and DNA synthesis inhibitors. Enrichment analysis confirmed targeting to gene sets associated with these annotated targets, and to pathways/biological processes associated with DNA synthesis/damage/repair, Proteases/proteasome and metabolism._Prediction of novel targets for some compounds revealed enrichment in pathways associated with neural cell function and AD. The findings suggest that image-based phenotyping by morphological profiling distinguishes SORL1-/- NPCs from isogenic wild-type lines, and predicts treatment responses that rescue SORL1-/--associated cellular signatures that are relevant to both SORLA function and AD. Overall, this work suggests that i) a quantitative phenotypic metric can distinguish iPSC-derived SORL1-/- NPCs from isogenic wild-type control and ii) phenotypic screening combined with multiparametric high-content image analysis is a viable option for drug repurposing and discovery in this human neural cell model of Alzheimers disease.

neuroscience↗

bioRxiv2021

Loss of SORCS2 is associated with neuronal DNA double-strand breaks

SORCS2 is one of five proteins that constitute the Vps10p-domain receptor family. Members of this family play important roles in cellular processes linked to neuronal survival, differentiation and function. Genetic and functional studies implicate SORCS2 in cognitive function, as well as in neurodegenerative and psychiatric disorders. DNA damage and DNA repair deficits are linked to ageing and neurodegeneration, and transient neuronal DNA double-strand breaks (DSBs) also occur as a result of neuronal activity. Here, we report a novel role for SORCS2 in DSB formation. We show that SorCS2 loss is associated with elevated DSB levels in the mouse dentate gyrus and that knocking out SORCS2 in a human neuronal cell line increased Topoisomerase II{beta}-dependent DSB formation and reduced neuronal viability. Neuronal stimulation had no impact on levels of DNA breaks in vitro, suggesting that the observed differences may not be the result of aberrant neuronal activity in these cells. Our findings are consistent with studies linking the VPS10 receptors and DNA damage to neurodegenerative conditions.

neuroscience↗

bioRxiv2021

SorCS2 deletion leads to altered neuronal lysosome activity

Vps10p domain receptors are important for regulating intracellular protein sorting within the central nervous system and as such constitute risk factors for different brain pathologies. Here, we show that removal of SorCS2 leads to altered lysosomal activity in mouse primary neurons. SorCS2-/- neurons show elevated lysosomal markers such as LAMP1 and acidic hydrolases including cathepsin B and D. Despite increased levels, SorCS2-/- neurons fail to degrade cathepsin specific substrates in a live context. SorCS2-deficient mice present an increase in lysolipids, which may contribute to membrane permeabilization and increased susceptibility to lysosomal stress. Our findings highlight SorCS2 as an important factor for a balanced neuronal lysosome milieu.

cell biology↗