Biology subjects

Vaegter, C. B.

Publications and source records attributed to Vaegter, C. B..

4 recordsLinked to original sources

bioRxiv2021

Comparative transcriptional analysis of the satellite glial cell injury response

Satellite glial cells (SGCs) tightly surround and support primary sensory neurons in the peripheral nervous system and are increasingly recognized for their involvement in the development of neuropathic pain following nerve injury. The SGCs are difficult to investigate due to their flattened shape and tight physical connection to neurons in vivo and their rapid changes in phenotype and protein expression when cultured in vitro. Consequently, several aspects of SGC function under normal conditions as well as after a nerve injury remain to be explored. The recent advance in single cell RNAseq technologies has enabled a new approach to investigate SGCs. Here we publish a dataset from mice subjected to sciatic nerve injury as well as a dataset from dorsal root ganglia cells after 3 days in culture. We use a meta-analysis approach to compare the injury response with that in other published datasets and conclude that SGCs share a common signature following sciatic nerve crush and sciatic ligation, involving transcriptional regulation of cholesterol biosynthesis. We also observed a considerable transcriptional change when culturing SGCs, suggesting that some differentiate into a specialised in vitro state, while others start resembling Schwann cell-like precursors. The datasets are available via the Broad Institute Single Cell Portal.

neuroscience↗

bioRxiv2021

α-Synuclein pathology in Parkinson disease activates homeostatic NRF2 anti-oxidant response

Circumstantial evidence points to a pathological role of alpha-synuclein (aSyn; gene symbol SNCA), conferred by aSyn misfolding and aggregation, in Parkinson disease (PD) and related synucleionpathies. Several findings in experimental models implicate perturbations in the tissue homeostatic mechanisms triggered by pathological aSyn accumulation, including impaired redox homeostasis, as significant contributors in the pathogenesis of PD. The nuclear factor erythroid 2-related factor (NRF2) is recognized as the master regulator of cellular anti-oxidant response, both under physiological as well as in pathological conditions. Using immunohistochemical analyses, we show a robust nuclear NRF2 accumulation in post-mortem PD midbrain, detected by NRF2 phosphorylation on serine residue 40 (nuclear active p-NRF2, S40). Curated gene expression analyses of four independent publicly available microarray datasets revealed considerable alterations in NRF2-responsive genes in the disease affected regions in PD, including substantia nigra, dorsal motor nucleus of vagus, locus coeruleus and globus pallidus. To further examine the putative role of pathological aSyn accumulation on nuclear NRF2 response, we employed a transgenic mouse model of synucleionopathy (M83 line, Prnp-SNCA*Ala53Thr), which manifest widespread aSyn pathology (phosphorylated aSyn; S129) in the nervous system following intramuscular inoculation of exogenous fibrillar aSyn. We observed strong immunodetection of nuclear NRF2 in neuronal populations harboring p-aSyn (S129), and found an aberrant anti-oxidant and inflammatory gene response in the affected neuraxis. Taken together, our data support the notion that pathological aSyn accumulation impairs the redox homeostasis in nervous system, and boosting neuronal anti-oxidant response is potentially a promising approach to mitigate neurodegeneration in PD and related diseases.

neuroscience↗

bioRxiv2020

SorCS1 binds the insulin receptor to enhance insulin sensitivity

Type 2 diabetes has reached endemic proportions and is a substantial burden for the affected patients and the society. Along with lifestyle factors, a number of genetic loci predisposing to type 2 diabetes have been identified, including SORCS1 that encodes the transmembrane receptor SorCS1. The ectodomain of SorCS1 (sol-SorCS1) is shed from plasma membranes but the biological function of this fragment is unknown. Here we show that sol-SorCS1 acts as a high-affinity binding partner for the insulin receptor to stabilize the receptor and increase insulin affinity, protein kinase B activation, and glucose uptake in myocytes. Sol-SorCS1 is liberated from adipocytes, and in diabetic patients the plasma concentration positively correlates with body mass index, but inversely with plasma glucose. In mouse models of insulin resistance, exogenous sol-SorCS1 restored insulin sensitivity. We conclude that sol-SorCS1 increases peripheral insulin sensitivity and propose sol-SorCS1 as a novel insulin sensitizing adipokine and potential antidiabetic agent.

physiology↗

bioRxiv2020

Endosomal trafficking is required for glycosylation and normal maturation of the Alzheimer's-associated protein sorLA

The sorting receptor sorLA encoded by the SORL1 gene is implicated in Alzheimers disease (AD) pathogenesis. Genetic studies have identified AD-associated SORL1 mutations and the expression of sorLA in AD brains is reported to be reduced. SorLA is a receptor of the retromer trafficking complex and functions at the endosome, and deficiency in sorLA phenocopies the endosomal pathologies found in AD. SorLA undergoes posttranslational modifications and maturation with ultimate ectodomain shedding, however knowledge of these processes remains limited. Here we demonstrate that sorLA exists at the cell membrane in two forms, an immature and a mature form, characterized by distinct N-glycosylation profiles. The mature sorLA form has acquired complex type N-glycans and is shed from the cell surface by the TACE juxtmembrane cleavage. The immature form of sorLA present at the cell surface is shown to have immature ER-type N-glycans (high-mannose type susceptible to endo H) and does not undergo shedding, however, upon endocytosis and recycling to the cell surface via endosomal trafficking pathways the immature sorLA form acquires complex-type N-glycans. These results suggest an unusual secretion model for sorLA whereby that immature sorLA first traffics to the cell membrane without acquiring Golgi processing of N-glycans, and only upon retrograde trafficking does sorLA acquire normal Golgi maturation of N-glycans and become susceptible to TACE regulated shedding. Supportive evidence for this model include a sorLA mutant with deficient endosomal trafficking and in vivo studies demonstrating requirement of retromer for sorLA trafficking in the brain of retromer VPS26 deficient mice. Collectively, our study establishes the role endosomal trafficking plays in sorLAs normal maturation, and point to impaired maturation as a signature of AD-associated sorLA dysfunction.

cell biology↗