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

Helwig, Michael; Hoshino, Akina; Berridge, Casey; Lee, Sang-Nam; Lorenzen, Nikolai; Otzen, Daniel E.; Eriksen, Jason L.; Lindberg, Iris

doi:10.1074/jbc.m112.417071

Cited by 52 publications

(54 citation statements)

References 54 publications

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“…This phenomenon has previously been demonstrated for the secretory proteins chromogranins A [39–41] and B [42, 43], proteins which have been proposed to assist in granule formation and efficient hormone storage. While these two secretory granule proteins do not structurally resemble 7B2, all have been termed “granins” due to the presence of a specific acidic amino acid motif [44], and 7B2 has known secretory chaperone effects [45, 46]. However, in our radiolabeling experiments of 7B2- and FGF23-transfected SW3 cells, we did not detect increased cellular FGF23 storage.…”

Section: Discussionmentioning

confidence: 54%

Posttranslational processing of FGF23 in osteocytes during the osteoblast to osteocyte transition

Yamamoto

Ramos‐Molina

Lick

et al. 2016

Bone

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FGF23 is an O-glycosylated circulating peptide hormone with a critical role in phosphate homeostasis; it is inactivated by cellular proprotein convertases in a pre-release degradative pathway. We have here examined the metabolism of FGF23 in a model bone cell line, IDG-SW3, prior to and following differentiation, as well as in regulated secretory cells. Labeling experiments showed that the majority of 35S-labeled FGF23 was cleaved to smaller fragments which were constitutively secreted by all cell types. Intact FGF23 was much more efficiently stored in differentiated than in undifferentiated IDG-SW3 cells. The prohormone convertase PC2 has recently been implicated in FGF23 degradation; however, FGF23 was not targeted to forskolin-stimulatable secretory vesicles in a regulated cell line, suggesting that it lacks a targeting signal to PC2-containing compartments. In vitro, PC1/3 and PC2, but not furin, efficiently cleaved glycosylated FGF23; surprisingly, PC5/6 accomplished a small amount of conversion. FGF23 has recently been shown to be phosphorylated by the kinase FAM20C, a process which was shown to reduce FGF23 glycosylation and promote its cleavage; our in vitro data, however, show that phosphorylation does not directly impact cleavage, as both PC5/6 and furin were able to efficiently cleave unglycosylated, phosphorylated FGF23. Using qPCR, we found that the expression of FGF23 and PC5/6, but not PC2 or furin, increased substantially following osteoblast to osteocyte differentiation. Western blotting confirmed the large increase in PC5/6 expression upon differentiation. FGF23 has been linked to a variety of bone disorders ranging from autosomal dominant hypophosphatemic rickets to chronic kidney disease. A better understanding of the biosynthetic pathway of this hormone may lead to new treatments for these diseases.

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Section: Discussionmentioning

confidence: 54%

Posttranslational processing of FGF23 in osteocytes during the osteoblast to osteocyte transition

Yamamoto

Ramos‐Molina

Lick

et al. 2016

Bone

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“…Previous work in our laboratory has shown that the secretory chaperone 7B2 not only colocalizes with amyloid plaques but also inhibits beta amyloid fibrillation [18]. Since 7B2 is abundant in the pancreas [26] we investigated the possibility that 7B2 may also inhibit hIAPP fibrillation.…”

Section: Resultsmentioning

confidence: 99%

“…As the tissue distributions of 7B2 and proSAAS are much broader than those of the convertases [17], additional functions are currently being investigated. The recent discovery of 7B2 as a potent inhibitor of beta amyloid and synuclein aggregation supports the idea that this family of chaperones may serve as general secretory chaperones, acting to prevent aggregation of proteins in AD and PD [18] and possibly in other diseases which involve amyloid formation.…”

Section: Introductionmentioning

confidence: 93%

Blockade of islet amyloid polypeptide fibrillation and cytotoxicity by the secretory chaperones 7B2 and proSAAS

et al. 2013

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The deposition of fibrillated human islet β-cell peptide islet amyloid polypeptide (hIAPP) into amyloid plaques is characteristic of the pathogenesis of islet cell death during type 2 diabetes. We investigated the effects of the neuroendocrine secretory proteins 7B2 and proSAAS on hIAPP fibrillation in vitro and on cytotoxicity. In vitro, 21-kDa 7B2 and proSAAS blocked hIAPP fibrillation. Structure-function studies showed that a central region within 21-kDa 7B2 is important in this effect and revealed the importance of the N-terminal region of proSAAS. Both chaperones blocked the cytotoxic effects of exogenous hIAPP on Rin5f cells; 7B2 generated by overexpression was also effective. ProSAAS and 7B2 may perform a chaperone role as secretory anti-aggregants in normal islet cell function and in type 2 diabetes.

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“…Overexpression or exogenous addition of a variety of chaperone proteins is efficacious in delaying or preventing amyloid fibril generation both in in vitro and, more recently, in vivo models of various amyloidogenic diseases (39)(40)(41). However, the chaperones tested to date are ubiquitously expressed, and thus far no neuron-specific chaperone protein has been shown to have antiaggregant activity against amyloidogenic diseases such as PD.…”

Section: Discussionmentioning

confidence: 99%

The neural chaperone proSAAS blocks α-synuclein fibrillation and neurotoxicity

Jarvela

Lam

Helwig

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Emerging evidence strongly suggests that chaperone proteins are cytoprotective in neurodegenerative proteinopathies involving protein aggregation; for example, in the accumulation of aggregated α-synuclein into the Lewy bodies present in Parkinson’s disease. Of the various chaperones known to be associated with neurodegenerative disease, the small secretory chaperone known as proSAAS (named after four residues in the amino terminal region) has many attractive properties. We show here that proSAAS, widely expressed in neurons throughout the brain, is associated with aggregated synuclein deposits in the substantia nigra of patients with Parkinson’s disease. Recombinant proSAAS potently inhibits the fibrillation of α-synuclein in an in vitro assay; residues 158–180, containing a largely conserved element, are critical to this bioactivity. ProSAAS also exhibits a neuroprotective function; proSAAS-encoding lentivirus blocks α-synuclein-induced cytotoxicity in primary cultures of nigral dopaminergic neurons, and recombinant proSAAS blocks α-synuclein–induced cytotoxicity in SH-SY5Y cells. Four independent proteomics studies have previously identified proSAAS as a potential cerebrospinal fluid biomarker in various neurodegenerative diseases. Coupled with prior work showing that proSAAS blocks β-amyloid aggregation into fibrils, this study supports the idea that neuronal proSAAS plays an important role in proteostatic processes. ProSAAS thus represents a possible therapeutic target in neurodegenerative disease.

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

Cited by 52 publications

References 54 publications

Posttranslational processing of FGF23 in osteocytes during the osteoblast to osteocyte transition

Posttranslational processing of FGF23 in osteocytes during the osteoblast to osteocyte transition

Blockade of islet amyloid polypeptide fibrillation and cytotoxicity by the secretory chaperones 7B2 and proSAAS

The neural chaperone proSAAS blocks α-synuclein fibrillation and neurotoxicity

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