The Biological and Chemical Basis for Tissue-Selective Amyloid Disease

Sekijima, Yoshiki; Wiseman, R. Luke; Matteson, Jeanne; Hammarström, Per; Miller, Sean R; Sawkar, Anu R.; Balch, William E.; Kelly, Jeffery W.

doi:10.1016/j.cell.2005.01.018

Cited by 423 publications

(589 citation statements)

References 51 publications

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“…[1][2][3][4][5][6][7][8][9][10]23,[33][34][35][36][37][43][44][45] The prevention of amyloidogenesis by a kinetic stabilizer approach has recently been demonstrated to halt the progression of nervous system degeneration in familial amyloid polyneuropathy associated with the amyloidogenesis of transthyretin. Thus, it is logical that the removal of protein aggregates would be crucial for protein homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Discovery and characterization of a mammalian amyloid disaggregation activity

Murray¹,

Solomon²,

Wang³

et al. 2010

Protein Science

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The formation of amyloid, a cross-b-sheet fibrillar aggregate, is associated with a variety of aging-associated degenerative diseases. Herein, we report the existence of a mammalian amyloid disaggregase activity that is present in all tissues and cell types tested. Homogenates from mammalian tissues and cell lines are able to disaggregate amyloid fibrils composed of amyloid b (Ab) 1-40 or the 8 kDa plasma gelsolin fragment. The mammalian disaggregase activity is sensitive to proteinase K digestion and can be uncoupled from proteolysis activity using a protease inhibitor cocktail. Amyloid disaggregation and proteolysis activities are remarkably resistant to changes in temperature and pH. Identification and manipulation of the proteins responsible for the amyloid disaggregation/degradation activities offers the possibility of ameliorating aggregation-associated diseases.

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Section: Discussionmentioning

confidence: 99%

Discovery and characterization of a mammalian amyloid disaggregation activity

Murray¹,

Solomon²,

Wang³

et al. 2010

Protein Science

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“…This is unlikely to represent a loss-of-function phenotype because the MKKS-knockout mouse shows BBS phenotypes but not MKKS phenotypes (Fath et al, 2005). Sekijima et al (2005) recently demonstrated that the thermodynamic and kinetic instability of transthyretin, a protein known to cause familial amyloidosis, affects the severity of the symptoms and that the most unstable mutants are less toxic than the moderately unstable mutants because the former undergo endoplasmic reticulum (ER)-associated protein degradation. In the MKKS mutants, G345E was more strongly recognized by cytosolic molecular chaperones and more easily degraded than Y37C.…”

Section: Discussionmentioning

confidence: 99%

MKKS Is a Centrosome-shuttling Protein Degraded by Disease-causing Mutations via CHIP-mediated Ubiquitination

Hirayama

Yamazaki²,

Kitamura³

et al. 2008

MBoC

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McKusick-Kaufman syndrome (MKKS) is a recessively inherited human genetic disease characterized by several developmental anomalies. Mutations in the MKKS gene also cause Bardet-Biedl syndrome (BBS), a genetically heterogeneous disorder with pleiotropic symptoms. However, little is known about how MKKS mutations lead to disease. Here, we show that disease-causing mutants of MKKS are rapidly degraded via the ubiquitin-proteasome pathway in a manner dependent on HSC70 interacting protein (CHIP), a chaperone-dependent ubiquitin ligase. Although wild-type MKKS quickly shuttles between the centrosome and cytosol in living cells, the rapidly degraded mutants often fail to localize to the centrosome. Inhibition of proteasome functions causes MKKS mutants to form insoluble structures at the centrosome. CHIP and partner chaperones, including heat-shock protein (HSP)70/heat-shock cognate 70 and HSP90, strongly recognize MKKS mutants. Modest knockdown of CHIP by RNA interference moderately inhibited the degradation of MKKS mutants. These results indicate that the MKKS mutants have an abnormal conformation and that chaperone-dependent degradation mediated by CHIP is a key feature of MKKS/BBS diseases. INTRODUCTIONMcKusick-Kaufman syndrome (MKKS) is a recessively inherited human genetic disease predominantly characterized by developmental anomalies, including vaginal atresia with hydrometrocolpos, polydactyly, and congenital heart defects (McKusick et al., 1964). The MKKS gene encodes a 570-amino acid polypeptide with weak but significant similarity to group II chaperonins . Mutations in the MKKS gene also cause Bardet-Biedl syndrome (BBS), a genetically heterogeneous disorder characterized by obesity, retinal dystrophy, polydactyly, mental retardation, renal malformation, and hypogenitalism (Beales et al., 1999), and thus MKKS is also called BBS6. The MKKS mRNA is widely expressed in various tissues, including those affected by MKKS and BBS diseases . Although more than 10 mutations in the MKKS gene have been identified in patients (Beales et al., 2001;Slavotinek et al., 2002), little is known about how they cause MKKS and BBS.Twelve of the genes that are responsible for BBS (BBS1-12) have been identified so far, and the products of several of these genes have been suggested to be involved in intraflagellar transport in cilia and intracellular trafficking in the cytosol Badano et al., 2005;Beales, 2005;Blacque and Leroux, 2006). Cargo-carrying motors play crucial roles in intraflagellar and intracellular transport systems by bidirectionally moving on microtubules, and BBS4 interacts with the dynactin complex, which mediates interactions between cargoes and the dynein motor (Kim et al., 2004). Retrograde transport of melanosomes in zebrafish is slowed by knockdown of BBS2 or BBS4-8 (Yen et al., 2006), whereas mutations in Caenorhabditis elegans BBS7 and BBS8 cause delays in intraflagellar transport driven by kinesin motors (Ou et al., 2005). The Chlamydomonas homologue of BBS5 is essential for flagellum formation (Li et al., ...

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“…The process of amyloidogenesis is causatively linked to numerous human diseases, many of which are associated with neurodegeneration (1-3). To date, all of the TTR variants associated with familial amyloidosis that have had their folding energetics characterized-21 of them-are destabilized relative to WT TTR, based on the observation that their denaturation transitions occur at lower concentrations of urea than WT TTR (7)(8)(9)(10)(11)(12)(13)(14)(15). TTR is tetrameric under physiological conditions.…”

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Quantification of the Thermodynamically Linked Quaternary and Tertiary Structural Stabilities of Transthyretin and Its Disease-Associated Variants: The Relationship between Stability and Amyloidosis

2008

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Urea denaturation studies were carried out as a function of transthyretin (TTR) concentration to quantify the thermodynamically linked quaternary and tertiary structural stability and to better understand the relationship between mutant folding energetics and amyloid disease phenotype. Urea denaturation of TTR involves at least two equilibria-dissociation of tetramers into folded monomers, and monomer unfolding. To deal with the thermodynamic linkage of these equilibria, we analyzed concentration-dependent denaturation data by global fitting to an equation that simultaneously accounts for the two-step denaturation process. Using this method, the quaternary and tertiary structural stabilities of well-behaved TTR sequences, wild type (WT) TTR and the disease-associated variant V122I, were scrutinized. The V122I variant is linked to late onset familial amyloid cardiomyopathy, the most common familial TTR amyloid disease. V122I TTR exhibits a destabilized quaternary structure and a stable tertiary structure relative to WT TTR. Three other variants of TTR were also examined, L55P, V30M, and A25T TTR. The L55P mutation is associated with the most aggressive familial TTR amyloid disease. L55P TTR has a complicated denaturation pathway that includes dimers and trimers, and so globally fitting its concentration-dependent urea denaturation data yielded error-laden estimates of stability parameters. Nevertheless, it is clear that L55P TTR is substantially less stable than WT TTR, primarily because its tertiary structure is unstable, although its quaternary structure is destabilized as well. V30M is the most common mutation associated with neuropathic forms of TTR amyloid disease. V30M TTR is certainly destabilized relative to WT TTR, but like L55P TTR it has a complex denaturation pathway that cannot be fit to the aforementioned two-step denaturation model. Literature data suggest that V30M † This research was supported by NIH Grant DK46335, the Skaggs Institute for Chemical Biology, and the Lita Annenberg Hazen Foundation. A.R.H.B. was supported by NIH Grants T32-AG00080 and F32-GM067348. *To whom correspondence should be addressed. Phone: (858) 784-9601; Fax: (858) 784-9610; E-mail: epowers@scripps.edu, jkelly@scripps.edu. 1 Abbreviations. TTR, transthyretin; WT, wild-type; M-TTR, a monomeric variant of transthyretin harboring F87M and L110M mutations; SSA, senile systemic amyloidosis; FAP, familial amyloid polyneuropathy; FAC, familial amyloid cardiomyopathy; Tris, Tris (hydroxymethyl)aminomethane; EDTA, ethylenediamine-N,N,N′,N′-tetraacetic acid; DTT, dithiothreitol; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis; CSF, cerebrospinal fluid. SUPPORTING INFORMATION AVAILABLEPlots showing the global fit of our three state model (native tetramer, folded monomer, unfolded monomer) to the concentration-dependent urea denaturation data for WT, V122I, and L55P TTR, and a plot showing the relatively poor global fit to a two state model (native tetramer, unfolded monomer) for WT TTR. This material is ...

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The Biological and Chemical Basis for Tissue-Selective Amyloid Disease

Cited by 423 publications

References 51 publications

Discovery and characterization of a mammalian amyloid disaggregation activity

Discovery and characterization of a mammalian amyloid disaggregation activity

MKKS Is a Centrosome-shuttling Protein Degraded by Disease-causing Mutations via CHIP-mediated Ubiquitination

Quantification of the Thermodynamically Linked Quaternary and Tertiary Structural Stabilities of Transthyretin and Its Disease-Associated Variants: The Relationship between Stability and Amyloidosis

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