A5075685562- Alzheimer's disease research and treatments
- Cellular transport and secretion
- 14-3-3 protein interactions
- Retinal Development and Disorders
- Signaling Pathways in Disease
- Machine Learning in Bioinformatics
- RNA Research and Splicing
- Monoclonal and Polyclonal Antibodies Research
- Protease and Inhibitor Mechanisms
- Lipoproteins and Cardiovascular Health
- Bioinformatics and Genomic Networks
- Cell Adhesion Molecules Research
- Cholinesterase and Neurodegenerative Diseases
- Neuroscience and Neuropharmacology Research
- Nerve injury and regeneration
- Blood Coagulation and Thrombosis Mechanisms
- Endoplasmic Reticulum Stress and Disease
- Neurogenesis and neuroplasticity mechanisms
- Neuroinflammation and Neurodegeneration Mechanisms
- HER2/EGFR in Cancer Research
- Protein Kinase Regulation and GTPase Signaling
- Glycosylation and Glycoproteins Research
- Nuclear Receptors and Signaling
- Computational Drug Discovery Methods
- Amyloidosis: Diagnosis, Treatment, Outcomes
Aarhus University
2014-2024
Danish National Research Foundation
2021-2022
Danish Diabetes Academy
2019-2022
Lundbeck Foundation
2010-2019
European Bioinformatics Institute
2015
Aarhus University Hospital
2014
Alexandra Institute (Denmark)
2010
Vestergaard (Switzerland)
2010
Max Delbrück Center
2003-2009
Mental Health Research Institute
2006
sorLA (sorting protein-related receptor) is a type-1 membrane protein of unknown function that expressed in neurons. Its homology to sorting receptors shuttle between the plasma membrane, endosomes, and Golgi suggests related neuronal trafficking processes. Because expression reduced brain patients with Alzheimer's disease (AD), we tested involvement this receptor intracellular transport processing amyloid precursor (APP) β-peptide (Aβ), principal component senile plaques. We demonstrate...
sorLA is a sorting receptor for amyloid precursor protein (APP) genetically linked to Alzheimer's disease (AD). Retromer, an adaptor complex in the endosome-to-Golgi retrieval pathway, has been implicated APP transport because retromer deficiency leads aberrant and processing levels of proteins are altered AD. Here we report that functionally interact neurons control trafficking amyloidogenic APP. We have identified sequence (FANSHY) cytoplasmic domain recognized by VPS26 subunit complex....
Loss of the Sortilin-related receptor 1 (SORL1) gene seems to act as a causal event for Alzheimer's disease (AD). Recent studies have established that loss SORL1, well mutations in autosomal dominant AD genes APP and PSEN1/2, pathogenically converge by swelling early endosomes, AD's cytopathological hallmark. Acting together with retromer trafficking complex, SORL1 has been shown regulate recycling amyloid precursor protein (APP) out endosome, contributing endosomal misprocessing. We...
Megalin is a low-density lipoprotein receptor-related protein (LRP2)expressed in the neuroepithelium and yolk sac of early embryo. Absence megalin expression knockout mice results holoprosencephaly,indicating an essential yet unidentified function forebrain development. We used with complete or conditional gene inactivation embryo to demonstrate that but not crucial for brain During development, deficiency leads increase bone morphogenic (Bmp) 4 signaling rostral dorsal neuroepithelium,...
SorLA has been recognized as a novel sorting receptor that regulates trafficking and processing of the amyloid precursor protein (APP) represents significant risk factor for sporadic Alzheimer disease. Here, we investigated cellular mechanisms control intracellular sorLA their relevance APP processing. We demonstrate acts retention in trans-Golgi compartments/trans-Golgi network, preventing release into regular pathways. Proper localization activity are dependent on functional interaction...
sorLA is a recently identified neuronal receptor for amyloid precursor protein (APP) that known to interact with APP and affect its intracellular transport processing. Decreased levels of in the brain Alzheimer's disease (AD) patients elevated amyloid-β peptide (Aβ) sorLA-deficient mice point importance this neurodegenerative disorder. We analyzed cleavage an APP-shedding assay found both and, surprisingly, tail construct inhibited β-site APP-cleaving enzyme (BACE)-dependent manner. In line...
SorLA/LR11 is a sorting receptor that regulates the intracellular transport and processing of amyloid precursor protein (APP) in neurons. SorLA/LR11-mediated binding results sequestration APP Golgi protection from into amyloid-β peptide (Aβ), principal component senile plaques Alzheimer's disease (AD). To gain insight molecular mechanisms governing sorLA interaction, we have dissected respective interacting domains. Using fluorescence resonance energy transfer (FRET) based assay proximity,...
Alzheimer's disease (AD) is the most prevalent form of dementia, resulting in progressive neuronal death and debilitating damage to brain loci that mediate memory higher cognitive function. While pathogenic genetic mutations have been implicated ∼2% AD cases, proximal events underlie common, sporadic are incompletely understood. Converging lines evidence from human neuropathology, basic biology, genetics loss multifunctional receptor LR11 (also known as SORLA SORL1) pathogenesis. Cell-based...
Sortilin-related receptor with A-type repeats (SORLA) is a sorting that impairs processing of amyloid precursor protein (APP) to soluble (s) APP and the β-peptide in cultured neurons poorly expressed patients Alzheimer disease (AD). Here, we evaluated consequences Sorla gene defects on brain anatomy function using mouse models deficiency. In line protective role for SORLA metabolism, lack results increased amyloidogenic endogenous aggravated plaque deposition when introduced into PDAPP mice...
The development and progression of Alzheimer's disease is linked to excessive production toxic amyloid-β peptide, initiated by β-secretase cleavage the amyloid precursor protein (APP). In contrast, soluble APPα (sAPPα) generated α-secretase known stimulate dendritic branching enhance synaptic function. Regulation APP processing, shift from neurotrophic neurotoxic metabolism remains poorly understood, but cellular localization its interaction with various receptors considered important. We...
Abstract The human epidermal growth factor receptor 2 (HER2) is an oncogene targeted by several kinase inhibitors and therapeutic antibodies. While the endosomal trafficking of many other tyrosine kinases known to regulate their oncogenic signalling, prevailing view on HER2 that this predominantly retained cell surface. Here, we find sortilin-related 1 (SORLA; SORL1 ) co-precipitates with in cancer cells regulates subcellular distribution promoting recycling back plasma membrane. SORLA...
Whether or how the pathogenic disruptions in endosomal trafficking observed Alzheimer's disease (AD) are linked to its anatomical vulnerability remain unknown. Here, we began addressing these questions by showing that neurons enriched with a second retromer core, organized around VPS26b, differentially dedicated recycling. Next, imaging mouse models, show trans-entorhinal cortex, region most vulnerable AD, is susceptible VPS26b depletion—a finding validated electrophysiology,...
The established causal genes in Alzheimer's disease (AD), APP, PSEN1, and PSEN2, are functionally characterized using biomarkers, capturing an vivo profile reflecting the disease's initial preclinical phase. Mutations SORL1, encoding endosome recycling receptor SORLA, found 2%–3% of individuals with early-onset AD, SORL1 haploinsufficiency appears to be for AD. To test whether can function as AD gene, we use CRISPR-Cas9-based gene editing develop a model Göttingen minipigs, taking advantage...
SORL1 , the gene encoding large multidomain SORLA protein, has emerged as only fourth that when mutated can by itself cause Alzheimer’s disease (AD), and a reliably linked to both early- late-onset forms of disease. is known interact with endosomal trafficking regulatory complex called retromer in regulating recycling cargo, including amyloid precursor protein (APP) glutamate receptor GluA1. Nevertheless, SORLA’s precise structural–functional relationship tubules remains unknown. Here, we...
The apolipoprotein (apo) E receptor-2 (apoER2) is a member of the low density lipoprotein receptor gene family and an important regulator neuronal migration. It acts as for signaling factor Reelin provides positional cues to neurons that migrate their proper position in developing brain. Besides brain formation defects, apoER2-deficient mice also exhibit male infertility. role reproduction, however, remained unclear. Here we demonstrate apoER2 highly expressed initial segment epididymis,...
Blocking of sortilin ligand binding prevents neuropathic pain by inhibiting BDNF-induced spinal KCC2 down-regulation.