The lectin OS-9 delivers mutant neuroserpin to endoplasmic reticulum associated degradation in familial encephalopathy with neuroserpin inclusion bodies

Schipanski, Angela; Oberhauser, Felix; Neumann, Melanie; Lange, Adam; Szalay, Beata; Krasemann, Susanne; Leeuwen, Fred W. van; Galliciotti, Giovanna; Glatzel, Markus

doi:10.1016/j.neurobiolaging.2014.04.002

Cited by 24 publications

(31 citation statements)

References 50 publications

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“…A1AT mutants that are retained in the ER interact with the chaperones BiP, GRP94, CNX, and HYOU1/GRP170 (Schmidt & Perlmutter, ), which are also interactors of ER‐β. Furthermore, OS‐9 and GRP94 have previously been shown to be involved in the delivery of both neuroserpin and A1AT mutants to SEL1L for ERAD (Christianson et al , ; Schipanski et al , ). OS‐9 is a lectin that has been suggested to have a dual function in ER quality control: the retention of misfolded proteins in the ER lumen and the delivery of misfolded proteins for ERAD (Bernasconi et al , ; Olzmann et al , ).…”

Section: Discussionmentioning

confidence: 99%

High capacity of the endoplasmic reticulum to prevent secretion and aggregation of amyloidogenic proteins

et al. 2017

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Protein aggregation is associated with neurodegeneration and various other pathologies. How specific cellular environments modulate the aggregation of disease proteins is not well understood. Here, we investigated how the endoplasmic reticulum (ER) quality control system handles β-sheet proteins that were designed to form amyloid-like fibrils. While these proteins undergo toxic aggregation in the cytosol, we find that targeting them to the ER (ER-β) strongly reduces their toxicity. ER-β is retained within the ER in a soluble, polymeric state, despite reaching very high concentrations exceeding those of ER-resident molecular chaperones. ER-β is not removed by ER-associated degradation (ERAD) but interferes with ERAD of other proteins. These findings demonstrate a remarkable capacity of the ER to prevent the formation of insoluble β-aggregates and the secretion of potentially toxic protein species. Our results also suggest a generic mechanism by which proteins with exposed β-sheet structure in the ER interfere with proteostasis.

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Section: Discussionmentioning

confidence: 99%

High capacity of the endoplasmic reticulum to prevent secretion and aggregation of amyloidogenic proteins

et al. 2017

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“…Schipanski et al . also showed that removal of both asparagine residues led to increased accumulation of G392E NS within the ER of HEK cells, but polymer formation was not assessed at great detail. Here we show that preventing glycosylation of wild type NS by mutating any of the sites to alanine led to mild polymerisation, higher for wild type/N321A NS, while removing both chains simultaneously caused a higher level of polymer formation.…”

Section: Discussionmentioning

confidence: 99%

Interactions between N‐linked glycosylation and polymerisation of neuroserpin within the endoplasmic reticulum

et al. 2015

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The neuronal serpin neuroserpin undergoes polymerisation as a consequence of point mutations that alter its conformational stability, leading to a neurodegenerative dementia called familial encephalopathy with neuroserpin inclusion bodies (FENIB). Neuroserpin is a glycoprotein with predicted glycosylation sites at asparagines 157, 321 and 401. We used site‐directed mutagenesis, transient transfection, western blot, metabolic labelling and ELISA to probe the relationship between glycosylation, folding, polymerisation and degradation of neuroserpin in validated cell models of health and disease. Our data show that glycosylation at N157 and N321 plays an important role in maintaining the monomeric state of neuroserpin, and we propose this is the result of steric hindrance or effects on local conformational dynamics that can contribute to polymerisation. Asparagine residue 401 is not glycosylated in wild type neuroserpin and in several polymerogenic variants that cause FENIB, but partial glycosylation was observed in the G392E mutant of neuroserpin that causes severe, early‐onset dementia. Our findings indicate that N401 glycosylation reports lability of the C‐terminal end of neuroserpin in its native state. This C‐terminal lability is not required for neuroserpin polymerisation in the endoplasmic reticulum, but the additional glycan facilitates degradation of the mutant protein during proteasomal impairment. In summary, our results indicate how normal and variant‐specific N‐linked glycosylation events relate to intracellular folding, misfolding, degradation and polymerisation of neuroserpin.

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“…Alternatively, secondary antibodies conjugated with IRDye 800CW or IRDye 680RD (1:10,000) (LI-COR Biosciences) were incubated for 1 h at room temperature and membranes were scanned using an Odyssey Infrared Imaging System (LI-COR Biosciences). Densitometric quantification was performed with Imager Gel Doc System and Quantity One software (Bio-Rad Laboratories) (Schipanski et al 2014) or using LI-COR Odyssey Software, version 2.0 and local background subtraction.…”

Section: Western Blotting and Densitometrymentioning

confidence: 99%

The serine protease inhibitor neuroserpin is required for normal synaptic plasticity and regulates learning and social behavior

et al. 2017

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The serine protease inhibitor neuroserpin regulates the activity of tissue-type plasminogen activator (tPA) in the nervous system. Neuroserpin expression is particularly prominent at late stages of neuronal development in most regions of the central nervous system (CNS), whereas it is restricted to regions related to learning and memory in the adult brain. The physiological expression pattern of neuroserpin, its high degree of colocalization with tPA within the CNS, together with its dysregulation in neuropsychiatric disorders, suggest a role in formation and refinement of synapses. In fact, studies in cell culture and mice point to a role for neuroserpin in dendritic branching, spine morphology, and modulation of behavior. In this study, we investigated the physiological role of neuroserpin in the regulation of synaptic density, synaptic plasticity, and behavior in neuroserpin-deficient mice. In the absence of neuroserpin, mice show a significant decrease in spine-synapse density in the CA1 region of the hippocampus, while expression of the key postsynaptic scaffold protein PSD-95 is increased in this region. Neuroserpin-deficient mice show decreased synaptic potentiation, as indicated by reduced long-term potentiation (LTP), whereas presynaptic paired-pulse facilitation (PPF) is unaffected. Consistent with altered synaptic plasticity, neuroserpin-deficient mice exhibit cognitive and sociability deficits in behavioral assays. However, although synaptic dysfunction is implicated in neuropsychiatric disorders, we do not detect alterations in expression of neuroserpin in fusiform gyrus of autism patients or in dorsolateral prefrontal cortex of schizophrenia patients. Our results identify neuroserpin as a modulator of synaptic plasticity, and point to a role for neuroserpin in learning and memory.

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The lectin OS-9 delivers mutant neuroserpin to endoplasmic reticulum associated degradation in familial encephalopathy with neuroserpin inclusion bodies

Cited by 24 publications

References 50 publications

High capacity of the endoplasmic reticulum to prevent secretion and aggregation of amyloidogenic proteins

High capacity of the endoplasmic reticulum to prevent secretion and aggregation of amyloidogenic proteins

Interactions between N‐linked glycosylation and polymerisation of neuroserpin within the endoplasmic reticulum

The serine protease inhibitor neuroserpin is required for normal synaptic plasticity and regulates learning and social behavior

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