Generation of aggregation prone N-terminally truncated amyloid β peptides by meprin β depends on the sequence specificity at the cleavage site

Schönherr, Caroline; Bien, Jessica; Isbert, Simone; Wichert, Rielana; Prox, Johannes; Altmeppen, Hermann; Kumar, Sathish; Walter, Jochen; Lichtenthaler, Stefan F.; Weggen, Sascha; Glatzel, Markus; Becker‐Pauly, Christoph; Pietrzik, Claus U.

doi:10.1186/s13024-016-0084-5

Cited by 68 publications

(82 citation statements)

References 75 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Sporadic PD accounts for more than 90% of PD cases (Lang and Lozano, 1998), and only less than 10% of familial PD cases are caused by monogenic mutations (Benitez et al, 2016). Mutations in the gene encoding α-synuclein (Polymeropoulos et al, 1997; Helferich et al, 2015; Majbour et al, 2016; Schonherr et al, 2016) represent autosomal dominant familial PD, and mutations in genes encoding parkin (Kitada et al, 1998; Cha et al, 2015), UCHL1 (Leroy et al, 1998; Maraganore et al, 1999), DJ-1 (Bonifati et al, 2003), PINK1 (Valente et al, 2004), and LRRK2 (Zimprich et al, 2004; Saha et al, 2015) cause autosomal recessive familial PD.…”

Section: Abnormal Protein Aggregation In Neurodegenerative Diseasesmentioning

confidence: 99%

Dysregulation of Ubiquitin-Proteasome System in Neurodegenerative Diseases

Zheng

Huang

Zhang

et al. 2016

Front. Aging Neurosci.

251

171

View full text Add to dashboard Cite

The ubiquitin-proteasome system (UPS) is one of the major protein degradation pathways, where abnormal UPS function has been observed in cancer and neurological diseases. Many neurodegenerative diseases share a common pathological feature, namely intracellular ubiquitin-positive inclusions formed by aggregate-prone neurotoxic proteins. This suggests that dysfunction of the UPS in neurodegenerative diseases contributes to the accumulation of neurotoxic proteins and to instigate neurodegeneration. Here, we review recent findings describing various aspects of UPS dysregulation in neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease.

show abstract

Section: Abnormal Protein Aggregation In Neurodegenerative Diseasesmentioning

confidence: 99%

Dysregulation of Ubiquitin-Proteasome System in Neurodegenerative Diseases

Zheng

Huang

Zhang

et al. 2016

Front. Aging Neurosci.

251

171

View full text Add to dashboard Cite

show abstract

“…These structural features provide all requirements that meprin b must have to act as an ectodomain sheddase at the cell surface. Indeed, membrane-bound amyloid precursor protein (APP), for instance, is cleaved by meprin b, resulting in the release of sAPP-b fragments and neurotoxic Ab peptides (4,7,8). Many of the known substrates of meprin b have been identified by mass spectrometry (MS)-based proteomic approaches (9).…”

mentioning

confidence: 99%

Ectodomain shedding of CD99 within highly conserved regions is mediated by the metalloprotease meprin β and promotes transendothelial cell migration

et al. 2016

Self Cite

View full text Add to dashboard Cite

ABSTRACT:The adhesion molecule CD99 is essential for the transendothelial migration of leukocytes. In this study, we used biochemical and cellular assays to show that CD99 undergoes ectodomain shedding by the metalloprotease meprin b and subsequent intramembrane proteolysis by g-secretase. The cleavage site in CD99 was identified by mass spectrometry within an acidic region highly conserved through different vertebrate species. This finding fits perfectly to the unique cleavage specificity of meprin b with a strong preference for aspartate residues and suggests coevolution of protease and substrate. We hypothesized that limited CD99 cleavage by meprin b would alter cellular transendothelial migration (TEM) behavior in tissue remodeling processes, such as inflammation and cancer. Indeed, meprin b induced cell migration of Lewis lung carcinoma cells in an in vitro TEM assay. Accordingly, deficiency of meprin b in Mep1b 2/2 mice resulted in significantly increased CD99 protein levels in the lung. Therefore, meprin b could serve as a therapeutic target, given that in a proof-of-concept approach we showed accumulation of CD99 protein in lungs of meprin b inhibitortreated mice.-Bedau, T., Peters, F., Prox, J., Arnold, P., Schmidt, F., Finkernagel, M., Köllmann, S., Wichert, R., Otte, A., Ohler, A., Stirnberg, M., Lucius, R., Koudelka, T., Tholey, A., Biasin, V., Pietrzik, C. U., Kwapiszewska, G., Becker-Pauly, C. Ectodomain shedding of CD99 within highly conserved regions is mediated by the metalloprotease meprin b and promotes transendothelial cell migration. FASEB J. 31, 1226-1237 (2017). www.fasebj.orgRegulated intramembrane proteolysis (RIP) of cell adhesion molecules, such as junctional adhesion molecule (JAM)-A, intercellular adhesion molecule (ICAM)-1, and L-selectin, was shown to be essential for transendothelial migration (TEM) of inflammatory or cancer cells (1). Meprin b, a multidomain type I transmembrane metalloprotease, is an initiator of RIP, and structural studies revealed dimeric formation of the protease with the active site in proximity to the cell surface (2-4). In addition, meprin b can be shed from the cell surface by ADAM10/ 17, resulting in a soluble active protease, which for instance is important for mucus detachment in the small intestine (5). Meprin b is characterized by a unique cleavage specificity, with a preference for negatively charged amino acids (6). These structural features provide all requirements that meprin b must have to act as an ectodomain sheddase at the cell surface. Indeed, membrane-bound amyloid precursor protein (APP), for instance, is cleaved by meprin b, resulting in the release of sAPP-b fragments and neurotoxic Ab peptides (4,7,8). Many of the known substrates of meprin b have been identified by mass spectrometry (MS)-based proteomic approaches (9).

show abstract

“…Meprin ␤ knock-out also increased sAPP␤ in the soluble brain fraction as detected with a neoepitope-specific antibody, whereas conditioned medium from cells expressing APP SWE , which is a better substrate for BACE1 than wild-type APP (12), significantly altered the ratio of A␤2-40:A␤1-40 production, indicating direct competition between meprin ␤ and BACE1 for APP (27). Importantly, in the context of AD, A␤2-40 also showed increased aggregation propensity when compared with A␤1-40, implicating this species in the preferential production of oligomeric assemblies of A␤ (27). Still, in the brain, A␤2-X peptides are severalfold lower in abundance relative to A␤42 species.…”

Section: -Secretasementioning

confidence: 97%

“…Furthermore, cells expressing meprin ␤ produced significant amounts of A␤2-X even in the presence of a BACE1 inhibitor, whereas meprin ␤ inhibition significantly reduced its production (26). Further work has suggested that unlike BACE1, meprin ␤ cleaves APP at the cell surface and may directly compete with ADAM10 in vivo, as indicated by increased sAPP␣ in the soluble fractions derived from meprin ␤ knock-out mice brains (27). Meprin ␤ knock-out also increased sAPP␤ in the soluble brain fraction as detected with a neoepitope-specific antibody, whereas conditioned medium from cells expressing APP SWE , which is a better substrate for BACE1 than wild-type APP (12), significantly altered the ratio of A␤2-40:A␤1-40 production, indicating direct competition between meprin ␤ and BACE1 for APP (27).…”

Section: -Secretasementioning

confidence: 99%

“…Further work has suggested that unlike BACE1, meprin ␤ cleaves APP at the cell surface and may directly compete with ADAM10 in vivo, as indicated by increased sAPP␣ in the soluble fractions derived from meprin ␤ knock-out mice brains (27). Meprin ␤ knock-out also increased sAPP␤ in the soluble brain fraction as detected with a neoepitope-specific antibody, whereas conditioned medium from cells expressing APP SWE , which is a better substrate for BACE1 than wild-type APP (12), significantly altered the ratio of A␤2-40:A␤1-40 production, indicating direct competition between meprin ␤ and BACE1 for APP (27). Importantly, in the context of AD, A␤2-40 also showed increased aggregation propensity when compared with A␤1-40, implicating this species in the preferential production of oligomeric assemblies of A␤ (27).…”

Section: -Secretasementioning

confidence: 99%

See 1 more Smart Citation

A Greek Tragedy: The Growing Complexity of Alzheimer Amyloid Precursor Protein Proteolysis

Andrew

Kellett

Wang

et al. 2016

Journal of Biological Chemistry

150

122

View full text Add to dashboard Cite

Proteolysis of the amyloid precursor protein (APP) liberates various fragments including the proposed initiator of Alzheimer disease-associated dysfunctions, amyloid-␤. However, recent evidence suggests that the accepted view of APP proteolysis by the canonical ␣-, ␤-, and ␥-secretases is simplistic, with the discovery of a number of novel APP secretases (including ␦-and -secretases, alternative ␤-secretases) and additional metabolites, some of which may also cause synaptic dysfunction. Furthermore, various proteins have been identified that interact with APP and modulate its cleavage by the secretases. Here, we give an overview of the increasingly complex picture of APP proteolysis.Currently over 46 million people worldwide are living with dementia (see the Alzheimer's Disease International website) with Alzheimer disease (AD) 3 representing the most common form of dementia. In AD, the amyloid cascade hypothesis posits that amyloid-␤ (A␤), produced through the sequential proteolytic cleavage of the amyloid precursor protein (APP) by the ␤-and ␥-secretases, is a key molecule in initiating and propagating disease pathology including neurofibrillary tangle formation, neuronal cell loss, aberrant synaptic activity, and brain atrophy that lead to the clinically recognized symptoms of dementia (1). However, identification of the A␤ peptide 25 years ago has not yet led to the advent of a viable therapeutic strategy that can slow or halt the progression of AD. Recent studies have revealed new complexities in the proteolytic processing of APP, including the identification of novel secretases which generate APP metabolites that accumulate in the brains of AD patients and may contribute to the synaptic dysfunction observed in the disease. In addition, numerous proteins are being identified that interact with APP, modulating its proteolysis and A␤ production. These new APP secretases and metabolites, along with the APP interactors, may present novel therapeutic targets that are independent of direct modulation of the canonical secretases and that will need to be considered when evaluating the results from current A␤-directed therapies. In this Minireview, we summarize the recent developments in APP proteolysis focusing on the novel secretases, APP interactors, and APP metabolites that are impacting on our understanding of both APP biology and the neurodegenerative disease process. The Canonical ␣-, ␤-, and ␥-Secretases and APP FragmentsThe generally accepted model of APP proteolysis is that APP is processed by one of two distinct proteolytic pathways (Fig. 1A). In the amyloidogenic pathway, ␤-secretase, the ␤-site APP-cleaving enzyme 1 (BACE1), cleaves APP within the ectodomain and liberates a soluble proteolytic fragment, termed soluble APP␤ (sAPP␤), primarily in the endosomal system from the transmembrane APP holoprotein (2). The remaining C-terminal membrane-bound APP fragment, CTF␤, is subsequently cleaved by the presenilin (PS)-containing ␥-secretase multisubunit complex to liberate the A␤ peptide and the APP intrace...

show abstract

Generation of aggregation prone N-terminally truncated amyloid β peptides by meprin β depends on the sequence specificity at the cleavage site

Cited by 68 publications

References 75 publications

Dysregulation of Ubiquitin-Proteasome System in Neurodegenerative Diseases

Dysregulation of Ubiquitin-Proteasome System in Neurodegenerative Diseases

Ectodomain shedding of CD99 within highly conserved regions is mediated by the metalloprotease meprin β and promotes transendothelial cell migration

A Greek Tragedy: The Growing Complexity of Alzheimer Amyloid Precursor Protein Proteolysis

Contact Info

Product

Resources

About