The oxysterol 27-hydroxycholesterol (27OHC) is produced by the enzyme sterol 27-hydroxylase (Cyp27A1) and is mainly catabolized to 7α-Hydroxy-3-oxo-4-cholestenoic acid (7-HOCA) by the enzyme ...cytochrome P-450 oxysterol 7α-hydroxylase (Cyp7B1). 27OHC is mostly produced in the liver and can reach the brain by crossing the blood-brain barrier. A large body of evidence shows that CYP27A1 overexpression and high levels of 27OHC have a detrimental effect on the brain, causing cognitive and synaptic dysfunction together with a decrease in glucose uptake in mice. In this work, we analyzed two mouse models with high levels of 27OHC: Cyp7B1 knock-out mice and CYP27A1 overexpressing mice. Despite the accumulation of 27OHC in both models, Cyp7B1 knock-out mice maintained intact learning and memory capacities, neuronal morphology, and brain glucose uptake over time. Neurons treated with the Cyp7B1 metabolite 7-HOCA did not show changes in synaptic genes and 27OHC-treated Cyp7B1 knock-out neurons could not counteract 27OHC detrimental effects. This suggests that 7-HOCA and Cyp7B1 deletion in neurons do not mediate the neuroprotective effects observed in Cyp7B1 knock-out animals. RNA-seq of neuronal nuclei sorted from Cyp7B1 knock-out brains revealed upregulation of genes likely to confer neuroprotection to these animals. Differently from Cyp7B1 knock-out mice, transcriptomic data from CYP27A1 overexpressing neurons showed significant downregulation of genes associated with synaptic function and several metabolic processes. Our results suggest that the differences observed in the two models may be mediated by the higher levels of Cyp7B1 substrates such as 25-hydroxycholesterol and 3β-Adiol in the knock-out mice and that CYP27A1 overexpressing mice may be a more suitable model for studying 27-OHC-specific signaling. We believe that future studies on Cyp7B1 and Cyp27A1 will contribute to a better understanding of the pathogenic mechanisms of neurodegenerative diseases like Alzheimer’s disease and may lead to potential new therapeutic approaches.
•Cyp7B1 knock-out mice do not show cognitive and synaptic dysfunction, despite their high levels of 27-hydroxycholesterol.•In vitro treatments with Cyp7B1 metabolite 7-HOCA as well as Cyp7B1 silencing did not affect synaptic markers in neurons.•Transcriptomics data obtained from sorted cortical neuron nuclei from Cyp27Tg and CYP7B1KO mice reveal two distinct expression profiles.•Neurons from Cyp27Tg show significant downregulation of synaptic function and plasticity while Cyp7B1 knock-out primary neurons show upregulation of genes related to synaptic assembly, GABA-ergic signaling, and neuronal projection development.
Membranous glomerulonephritis (MGN) is a common cause of nephrotic syndrome in adults, mediated by glomerular antibody deposition to an increasing number of newly recognised antigens. Previous case ...reports have suggested an association between patients with anti-contactin-1 (CNTN1)-mediated neuropathies and MGN. In an observational study we investigated the pathobiology and extent of this potential cause of MGN by examining the association of antibodies against CNTN1 with the clinical features of a cohort of 468 patients with suspected immune-mediated neuropathies, 295 with idiopathic MGN, and 256 controls. Neuronal and glomerular binding of patient IgG, serum CNTN1 antibody and protein levels, as well as immune-complex deposition were determined. We identified 15 patients with immune-mediated neuropathy and concurrent nephrotic syndrome (biopsy proven MGN in 12/12), and 4 patients with isolated MGN from an idiopathic MGN cohort, all seropositive for IgG4 CNTN1 antibodies. CNTN1-containing immune complexes were found in the renal glomeruli of patients with CNTN1 antibodies, but not in control kidneys. CNTN1 peptides were identified in glomeruli by mass spectroscopy. CNTN1 seropositive patients were largely resistant to first-line neuropathy treatments but achieved a good outcome with escalation therapies. Neurological and renal function improved in parallel with suppressed antibody titres. The reason for isolated MGN without clinical neuropathy is unclear. We show that CNTN1, found in peripheral nerves and kidney glomeruli, is a common target for autoantibody-mediated pathology and may account for between 1 and 2% of idiopathic MGN cases. Greater awareness of this cross-system syndrome should facilitate earlier diagnosis and more timely use of effective treatment.
Membranous glomerulonephritis (MGN) is a common cause of nephrotic syndrome in adults, mediated by glomerular antibody deposition to an increasing number of newly recognised antigens. Previous case ...reports have suggested an association between patients with anti-contactin-1 (CNTN1)-mediated neuropathies and MGN. In an observational study we investigated the pathobiology and extent of this potential cause of MGN by examining the association of antibodies against CNTN1 with the clinical features of a cohort of 468 patients with suspected immune-mediated neuropathies, 295 with idiopathic MGN, and 256 controls. Neuronal and glomerular binding of patient IgG, serum CNTN1 antibody and protein levels, as well as immune-complex deposition were determined. We identified 15 patients with immune-mediated neuropathy and concurrent nephrotic syndrome (biopsy proven MGN in 12/12), and 4 patients with isolated MGN from an idiopathic MGN cohort, all seropositive for IgG4 CNTN1 antibodies. CNTN1-containing immune complexes were found in the renal glomeruli of patients with CNTN1 antibodies, but not in control kidneys. CNTN1 peptides were identified in glomeruli by mass spectroscopy. CNTN1 seropositive patients were largely resistant to first-line neuropathy treatments but achieved a good outcome with escalation therapies. Neurological and renal function improved in parallel with suppressed antibody titres. The reason for isolated MGN without clinical neuropathy is unclear. We show that CNTN1, found in peripheral nerves and kidney glomeruli, is a common target for autoantibody-mediated pathology and may account for between 1 and 2% of idiopathic MGN cases. Greater awareness of this cross-system syndrome should facilitate earlier diagnosis and more timely use of effective treatment.
Eliöille on kehittynyt sisäiseksi kelloksi vuorokausirytmi ajan mittaamista ja ajankulkuun reagoimista varten. Vuorokausirytmistä on eliöille etua, ja jonkinlainen sisäinen kello esiintyy jossain ...muodossa kaikilla aitotumallisilla ja osalla esitumallisista. Vuorokausirytmi mittaa ajanjaksoa, joka kestää noin vuorokauden. Vuorokausirytmi tahdistaa eliön kudokset ja elintoiminnot toimimaan rytmissä ympäristön vuorokaudenaikojen kanssa. Vuorokausirytmi toimii ympäristöstä riippumatta, eli se on elimistön sisäinen ominaisuus. Oikeassa tahdissa vuorokaudenaikojen kanssa pysyäkseen vuorokausirytmi vaatii kuitenkin ajastusta eli merkkisignaaleja ympäristöstä. Ilman näitä signaaleja rytmi alkaa edistämään tai jätättämään. Tärkein vuorokausirytmiä edistävä signaali on valo. Valon lisäksi tietyt kemialliset aineet, sosiaalinen vuorovaikutus ja fyysinen rasitus voivat ajastaa vuorokausirytmiä. Vuorokausirytmiä säädellään elimistössä hierakisella systeemillä, jonka ylimpänä keskuksena selkärankaisilla on aivojen hypotalamuksessa sijaitseva suprakiasmaattinen tumake. Valosignaalin ympäristöstä vastaanottavat verkkokalvolla tähän tehtävään erikoistuneet solut ja signaali kulkee suprakiasmaattiseen tumakkeeseen retinohypotalamista reittiä pitkin. Vuorokausirytmi syntyy suprakiasmaattisen tumakkeen soluissa tiettyjen geenien rytmisellä ilmentämisellä ja proteiinien pitoisuuksien muutoksilla. Tärkeimpiä vuorokausirytmiin vaikuttavia geenejä ovat clock ja bmal1. Gamma-aminovoihapolla on lisäksi suuri vaikutus vuorokausirytmin synnyssä ja säätelyssä suprakiasmaattisessa tumakkeessa. Häiriöt vuorokausirytmissä voivat olla terveydelle haitallisia, ja ne voivat altistaa ihmisen univaikeuksille sekä sairauksille kuten aineenvaihdunnan häiriöille ja masennukselle. Vuorokausirytmin häiriöitä voidaan hoitaa sekä lääke- että valohoidolla.
