The Collagen Chaperone HSP47 Is a New Interactor of APP that Affects the Levels of Extracellular Beta-Amyloid Peptides

Bianchi, F.; Camera, Paola; Ala, Ugo; Imperiale, Daniele; Migheli, Antonio; Boda, Enrica; Tempia, Filippo; Berto, Gaia; Bosio, Ylenia; Oddo, Salvatore; LaFerla, Frank M.; Taraglio, Stefano; Dotti, Carlos G.; Cunto, Ferdinando Di

doi:10.1371/journal.pone.0022370

Cited by 12 publications

(12 citation statements)

References 49 publications

(72 reference statements)

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“…Our immunohistochemical data show clear co-localization of 7B2 with aggregated proteins in neurodegenerative disease, indicating a potential functional relationship. A similar accumulation of chaperones within amyloid-like plaques in the brains of AD and PD patients has been reported for α-crystallin, HSP47, and clusterin (8, 35, 36). Interestingly, the distribution of immunoreactive 7B2 in diseased brain indicates that this protein may possess a higher affinity for non-aggregated Aβ 1–40 , Aβ 1–42 , and Aβ 1–40 and a lesser affinity for fully mature dense core plaques.…”

Section: Discussionsupporting

confidence: 77%

The Neuroendocrine Protein 7B2 Suppresses the Aggregation of Neurodegenerative Disease-related Proteins

Helwig

Hoshino

Berridge

et al. 2013

Journal of Biological Chemistry

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Background: The neuroendocrine protein 7B2 blocks the aggregation of certain secreted proteins.Results: 7B2 co-localizes with protein aggregates in Parkinson and Alzheimer disease brains; blocks the fibrillation of Aβ1–40, Aβ1–42, and α-synuclein; and blocks Aβ1–42-induced Neuro-2A cell death.Conclusion: 7B2 inhibits the cytotoxicity of Aβ1–42 by modulation of oligomer formation.Significance: 7B2 is a novel anti-aggregation secretory chaperone associated with neurodegenerative disease.

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Section: Discussionsupporting

confidence: 77%

The Neuroendocrine Protein 7B2 Suppresses the Aggregation of Neurodegenerative Disease-related Proteins

Helwig

Hoshino

Berridge

et al. 2013

Journal of Biological Chemistry

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“…A recent study found physical interaction and colocalization of SERPINH1 and amyloid precursor protein in neurons. SERPINH1 was also reported to be enriched in amyloid plaques in mouse brain and to modulate the levels of extracellular Aβ peptides in neuron cultures . However, in contrast with the results of previous studies of some ER chaperones such as BiP/GRP78 (glucose-regulated protein 78), calnexin, and calreticulin, − overexpression of SERPINH1 increased the level of secreted Aβ peptides, and reducing SERPINH1 expression with siRNA or chemically inhibiting its activity decreased the levels of secreted Aβ peptides in neuron cultures.…”

Section: Results and Discussioncontrasting

confidence: 64%

“…However, in contrast with the results of previous studies of some ER chaperones such as BiP/GRP78 (glucose-regulated protein 78), calnexin, and calreticulin, − overexpression of SERPINH1 increased the level of secreted Aβ peptides, and reducing SERPINH1 expression with siRNA or chemically inhibiting its activity decreased the levels of secreted Aβ peptides in neuron cultures. Taken together, these results predict that SERPINH1 affects the degradation of Aβ peptides in the extracellular environment by inhibiting proteases …”

Section: Results and Discussionmentioning

confidence: 64%

“…Taken together, these results predict that SERPINH1 affects the degradation of Aβ peptides in the extracellular environment by inhibiting proteases. 38 Another example of an ER-resident protein from our data set is PDIA3. PDIA3 is a protein disulfide isomerase 3 and is known as ERP57 (57-kD ER protein), GRP58 (58-kD glucoseregulated protein), and 1,25D3-MARRS (membrane-associated rapid response steroid-binding receptor).…”

Section: Er Proteinsmentioning

confidence: 99%

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Amyloid-Beta-Activated Human Microglial Cells Through ER-Resident Proteins

et al. 2014

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Microglial activation in the central nervous system is a key event in the neuroinflammation that accompanies neurodegenerative diseases such as Alzheimer's disease (AD). Among cytokines involved in microglial activation, amyloid β (Aβ) peptide is known to be a key molecule in the induction of diverse inflammatory products, which may lead to chronic inflammation in AD. However, proteomic studies of microglia in AD are limited due to lack of proper cell or animal model systems. In this study, we performed a proteomic analysis of Aβ-stimulated human microglial cells using SILAC (stable isotope labeling with amino acids in cell culture) combined with LC-MS/MS. Results showed that 60 proteins increased or decreased their abundance by 1.5 fold or greater. Among these, ER-resident proteins such as SERPINH1, PDIA6, PDIA3, and PPIB were revealed to be key molecular biomarkers of human microglial activation by validation of the proteomic results by immunostaining, PCR, ELISA, and Western blot. Taken together, our data suggest that ER proteins play an essential role in human microglial activation by Aβ and may be important molecular therapeutic targets for treatment of AD.

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“…However, the connections of our LCC with APP metabolism are not confined to the cleaving enzymes. Thus, the present LCC also contains the chaperone SERPINH1 (also HSP47) which has been demonstrated to regulate Aβ formation and the growth of amyloid plaques ( Figure 5 ) ( Bianchi et al, 2011 ).…”

Section: Discussionmentioning

confidence: 95%

The FOXP2-Driven Network in Developmental Disorders and Neurodegeneration

Oswald

Klöble

Ruland

et al. 2017

Front. Cell. Neurosci.

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The transcription repressor FOXP2 is a crucial player in nervous system evolution and development of humans and songbirds. In order to provide an additional insight into its functional role we compared target gene expression levels between human neuroblastoma cells (SH-SY5Y) stably overexpressing FOXP2 cDNA of either humans or the common chimpanzee, Rhesus monkey, and marmoset, respectively. RNA-seq led to identification of 27 genes with differential regulation under the control of human FOXP2, which were previously reported to have FOXP2-driven and/or songbird song-related expression regulation. RT-qPCR and Western blotting indicated differential regulation of additional 13 new target genes in response to overexpression of human FOXP2. These genes may be directly regulated by FOXP2 considering numerous matches of established FOXP2-binding motifs as well as publicly available FOXP2-ChIP-seq reads within their putative promoters. Ontology analysis of the new and reproduced targets, along with their interactors in a network, revealed an enrichment of terms relating to cellular signaling and communication, metabolism and catabolism, cellular migration and differentiation, and expression regulation. Notably, terms including the words “neuron” or “axonogenesis” were also enriched. Complementary literature screening uncovered many connections to human developmental (autism spectrum disease, schizophrenia, Down syndrome, agenesis of corpus callosum, trismus-pseudocamptodactyly, ankyloglossia, facial dysmorphology) and neurodegenerative diseases and disorders (Alzheimer’s, Parkinson’s, and Huntington’s diseases, Lewy body dementia, amyotrophic lateral sclerosis). Links to deafness and dyslexia were detected, too. Such relations existed for single proteins (e.g., DCDC2, NURR1, PHOX2B, MYH8, and MYH13) and groups of proteins which conjointly function in mRNA processing, ribosomal recruitment, cell–cell adhesion (e.g., CDH4), cytoskeleton organization, neuro-inflammation, and processing of amyloid precursor protein. Conspicuously, many links pointed to an involvement of the FOXP2-driven network in JAK/STAT signaling and the regulation of the ezrin–radixin–moesin complex. Altogether, the applied phylogenetic perspective substantiated FOXP2’s importance for nervous system development, maintenance, and functioning. However, the study also disclosed new regulatory pathways that might prove to be useful for understanding the molecular background of the aforementioned developmental disorders and neurodegenerative diseases.

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The Collagen Chaperone HSP47 Is a New Interactor of APP that Affects the Levels of Extracellular Beta-Amyloid Peptides

Cited by 12 publications

References 49 publications

The Neuroendocrine Protein 7B2 Suppresses the Aggregation of Neurodegenerative Disease-related Proteins

The Neuroendocrine Protein 7B2 Suppresses the Aggregation of Neurodegenerative Disease-related Proteins

Amyloid-Beta-Activated Human Microglial Cells Through ER-Resident Proteins

The FOXP2-Driven Network in Developmental Disorders and Neurodegeneration

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