Simon Glerup
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The SorCS2-derived macrocycle TT-P34 drives neuroprotection in animal models of neurodegeneration Open
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 en…
Nanobodies raised against the cytotoxic α-synuclein oligomer are oligomer-specific and promote its cellular uptake Open
Parkinson’s disease involves the accumulation of aggregates of ɑ-synuclein (ɑ-Syn), both as intracellular fibrils and as cytotoxic soluble oligomeric species (ɑSOs). No available nanobodies show exclusive preference for the oligomeric stat…
A triple serine motif in the intracellular domain of SorCS2 impacts its cellular signaling Open
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 mo…
View article: Reshaping the progranulin/sortilin interaction for targeted degradation of extracellular proteins
Reshaping the progranulin/sortilin interaction for targeted degradation of extracellular proteins Open
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 wi…
View article: Rare missense variants of the leukocyte common antigen related receptor (LAR) display reduced activity in transcellular adhesion and synapse formation
Rare missense variants of the leukocyte common antigen related receptor (LAR) display reduced activity in transcellular adhesion and synapse formation Open
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 connection…
View article: Lack of renoprotective effects by long-term PCSK9 and SGLT2 inhibition using alirocumab and empagliflozin in obese ZSF1 rats
Lack of renoprotective effects by long-term PCSK9 and SGLT2 inhibition using alirocumab and empagliflozin in obese ZSF1 rats Open
New treatments to slow kidney disease progression and reduce cardiovascular disease risk are needed for chronic kidney disease (CKD). We investigated the cholesterol-lowering PCSK9 inhibitor alirocumab as a new treatment for proteinuric CK…
A triple serine motif in the intracellular domains of sortilin-related receptors SorCS1-3 regulates neurotrophic activity Open
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 mo…
View article: Morphological profiling in human neural progenitor cells classifies hits in a pilot drug screen for Alzheimer’s disease
Morphological profiling in human neural progenitor cells classifies hits in a pilot drug screen for Alzheimer’s disease Open
Alzheimer’s disease accounts for 60–70% of dementia cases. Current treatments are inadequate and there is a need to develop new approaches to drug discovery. Recently, in cancer, morphological profiling has been used in combination with hi…
Alternative splicing regulates adaptor protein binding, trafficking, and activity of the Vps10p domain receptor SorCS2 in neuronal development Open
The Vps10p domain receptor SorCS2 is crucial for the development and function of the nervous system and essential for brain-derived neurotrophic factor (BDNF)-induced changes in neuronal morphology and plasticity. SorCS2 regulates the subc…
Proprotein convertase subtilisin/kexin type 9 targets megalin in the kidney proximal tubule and aggravates proteinuria in nephrotic syndrome Open
Proteinuria is a prominent feature of chronic kidney disease. Interventions that reduce proteinuria slow the progression of chronic kidney disease and the associated risk of cardiovascular disease. Here, we propose a mechanistic coupling b…
View article: Targeting PCSK9 to tackle cardiovascular disease
Targeting PCSK9 to tackle cardiovascular disease Open
Lowering blood cholesterol levels efficiently reduces the risk of developing atherosclerotic cardiovascular disease (ASCVD), including coronary artery disease (CAD), which is the main cause of death worldwide. CAD is caused by plaque forma…
Morphological profiling by Cell Painting in human neural progenitor cells classifies hit compounds in a pilot drug screen for Alzheimer’s disease Open
1 Abstract Alzheimer’s 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…
View article: PCSK9 deficiency alters brain lipid composition without affecting brain development and function
PCSK9 deficiency alters brain lipid composition without affecting brain development and function Open
PCSK9 induces lysosomal degradation of the low-density lipoprotein (LDL) receptor (LDLR) in the liver, hereby preventing removal of LDL cholesterol from the circulation. Accordingly, PCSK9 inhibitory antibodies and siRNA potently reduce LD…
Df(h22q11)/+ mouse model exhibits reduced binding levels of GABAA receptors and structural and functional dysregulation in the inhibitory and excitatory networks of hippocampus Open
The 22q11.2 hemizygous deletion confers high risk for multiple neurodevelopmental disorders. Inhibitory signaling, largely regulated through GABAA receptors, is suggested to serve a multitude of brain functions that are disrupted in the 22…
Sortilin Modulates Schwann Cell Signaling and Remak Bundle Regeneration Following Nerve Injury Open
Peripheral nerve regeneration relies on the ability of Schwann cells to support the regrowth of damaged axons. Schwann cells re-differentiate when reestablishing contact with the sprouting axons, with large fibers becoming remyelinated and…
Loss of SORCS2 is associated with neuronal DNA double-strand breaks Open
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 i…
Altered dopaminergic firing pattern and novelty response underlie ADHD-like behavior of SorCS2-deficient mice Open
Attention deficit hyperactivity disorder (ADHD) is the most frequently diagnosed neurodevelopmental disorder worldwide. Affected individuals present with hyperactivity, inattention, and cognitive deficits and display a characteristic parad…
Df(h15q13)/+ Mouse Model Reveals Loss of Astrocytes and Synaptic-Related Changes of the Excitatory and Inhibitory Circuits in the Medial Prefrontal Cortex Open
The 15q13.3 deletion is associated with multiple neurodevelopmental disorders including epilepsy, schizophrenia, and autism. The Df(h15q13)/+ mouse model was recently generated that recapitulates several phenotypic features of the human 15…
Reduced Alcohol Seeking and Withdrawal Symptoms in Mice Lacking the BDNF Receptor SorCS2 Open
Alcohol use disorder (AUD) is characterized by repetitive and uncontrolled intake of alcohol with severe consequences for affected individuals, their families and society as a whole. Numerous studies have implicated brain-derived neurotrop…
APOE4-mediated amyloid-β pathology depends on its neuronal receptor LRP1 Open
Carrying the ε4 allele of the APOE gene encoding apolipoprotein E (APOE4) markedly increases the risk for late-onset Alzheimer's disease (AD), in which APOE4 exacerbates the brain accumulation and subsequent deposition of amyloid-β (Aβ) pe…
Risk Locus Identification Ties Alcohol Withdrawal Symptoms to<i><span>SORCS</span>2</i> Open
Background Efforts to promote the cessation of harmful alcohol use are hindered by the affective and physiological components of alcohol withdrawal ( AW ), which can include life‐threatening seizures. Although previous studies of AW and re…
Cover Image, Volume 526, Issue 8 Open
The cover image, Simon Boggild et al., is based on the Research Article Highly segregated localization of the functionally related vps10p receptors sortilin and SorCS2 during neurodevelopment, DOI: 10.1002/cne.24403.
View article: Heparan sulfate proteoglycans present PCSK9 to the LDL receptor
Heparan sulfate proteoglycans present PCSK9 to the LDL receptor Open
Coronary artery disease is the main cause of death worldwide and accelerated by increased plasma levels of cholesterol-rich low-density lipoprotein particles (LDL). Circulating PCSK9 contributes to coronary artery disease by inducing lysos…