Proteostatic Hotspots in Amyloid Fibrils Protect Us from Neurodegeneration

Singh, Jitendra; Balch, William E.

doi:10.1016/j.devcel.2015.03.009

Cited by 5 publications

(3 citation statements)

References 10 publications

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“…Extracellular apolipoprotein J (Clusterin) is another chaperone found to co-localize with amyloid plaques in AD (Calero, et al, 2000) and has been shown to reduce Aβ aggregation and cytotoxicity in vitro (Yerbury, et al, 2007). Another protein domain suggested to function as a molecular chaperone and have anti-amyloid activity is the BRICHOS domain (Arosio, et al, 2016,Cohen, et al, 2015,Johansson, et al, 2006,Knight, et al, 2013,Sanchez-Pulido, et al, 2002,Singh and Balch, 2015,Willander, et al, 2011 found in the amyloid disease causing proproteins Bri2 (Sipe, et al, 2014,Vidal, et al, 1999,Vidal, et al, 2000 and proSP-C (Sipe, et al, 2014,H. Willander, et al, 2012a.…”

Section: The Complexity Of Protein Folding and How It Is Modulated Bymentioning

confidence: 99%

BRICHOS binds to a designed amyloid-forming β-protein and reduces proteasomal inhibition and aggresome formation

Dolfe

Winblad

Johansson

et al. 2016

Biochemical Journal

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The BRICHOS domain is associated with proliferative, degenerative and amyloid diseases, and it has been shown to inhibit fibril formation and toxicity of the Alzheimer's disease-associated amyloid β-peptide. ProSP-C (prosurfactant protein C) BRICHOS binds to stretches of hydrophobic amino acid residues, which are unfolded or in β-strand conformation, suggesting that it may have broad anti-amyloid activity. We have studied the effect of the proSP-C BRICHOS domain on the designed amyloidogenic β-sheet proteins β17 and β23. β17 expressed in the secretory pathway of HEK (human embryonic kidney)-293 cells forms intracellular inclusions, whereas β23 is rapidly degraded. Co-expression of BRICHOS leads to a reduction in β17 inclusion size and increased levels of soluble β17 and β23. Furthermore, BRICHOS interacts with the β-proteins intracellularly, reduces their ubiquitination and decreases aggresome formation and proteasomal inhibition. Collectively, these data suggest that BRICHOS is capable of delaying the aggregation process and toxicity of amyloidogenic proteins in a generic manner.

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Section: The Complexity Of Protein Folding and How It Is Modulated Bymentioning

confidence: 99%

BRICHOS binds to a designed amyloid-forming β-protein and reduces proteasomal inhibition and aggresome formation

Dolfe

Winblad

Johansson

et al. 2016

Biochemical Journal

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“…In addition, the mixture shows potent general molecular chaperone activity, measured as ability to prevent non-fibrillar aggregation of destabilized model substrate proteins 28 . The nature of the secondary nucleation sites is unknown and further studies of BRICHOS effects on Aβ42 fibrillization may provide valuable information on the way in which the secondary pathway functions 30 .…”

Section: Introductionmentioning

confidence: 99%

Bri2 BRICHOS client specificity and chaperone activity are governed by assembly state

et al. 2017

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Protein misfolding and aggregation is increasingly being recognized as a cause of disease. In Alzheimer’s disease the amyloid-β peptide (Aβ) misfolds into neurotoxic oligomers and assembles into amyloid fibrils. The Bri2 protein associated with Familial British and Danish dementias contains a BRICHOS domain, which reduces Aβ fibrillization as well as neurotoxicity in vitro and in a Drosophila model, but also rescues proteins from irreversible non-fibrillar aggregation. How these different activities are mediated is not known. Here we show that Bri2 BRICHOS monomers potently prevent neuronal network toxicity of Aβ, while dimers strongly suppress Aβ fibril formation. The dimers assemble into high-molecular-weight oligomers with an apparent two-fold symmetry, which are efficient inhibitors of non-fibrillar protein aggregation. These results indicate that Bri2 BRICHOS affects qualitatively different aspects of protein misfolding and toxicity via different quaternary structures, suggesting a means to generate molecular chaperone diversity.

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“…The BRICHOS domain binds to the fibrils and efficiently blocks the sites for secondary nucleation, leading to a significant decrease in the formation of toxic oligomers during Aβ42 aggregation (Fig. ) .…”

Section: Admentioning

confidence: 99%

Current and future treatment of amyloid diseases

et al. 2016

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There are more than 30 human proteins whose aggregation appears to cause degenerative maladies referred to as amyloid diseases or amyloidoses. These disorders are named after the characteristic cross-β-sheet amyloid fibrils that accumulate systemically or are localized to specific organs. In most cases current treatment is limited to symptomatic approaches and thus disease-modifying therapies are needed. Alzheimer’s disease is a neurodegenerative disorder with amyloid β-peptide (Aβ) plaques and tau neurofibrillary tangles as pathological hallmarks. Numerous clinical trials have been conducted with vaccines and small molecules to target Aβ formation and aggregation and also enhance Aβ clearance; so far such clinical trials have been unsuccessful. Novel strategies are therefore required and here we will discuss the possibility of utilizing the chaperone BRICHOS to prevent Aβ aggregation and toxicity. Type 2 diabetes mellitus is symptomatically treated with insulin. However the disease is linked to the aggregation and progressive accumulation of islet amyloid polypeptide and oligomers of this peptide are cytotoxic. Several compounds have been shown to inhibit islet amyloid aggregation and cytotoxicity in vitro. Future animal studies and clinical trials have to be be conducted to determine their efficacy in vivo. Transthyretin (TTR) amyloidoses are a group of systemic degenerative diseases involving multiple organ systems and caused by TTR aggregation. Liver transplantation decreases the generation of misfolded TTR and improves the quality of life for a subgroup of this patient population. Compounds that stabilize the natively folded, non-amyloidogenic, tetrameric conformation of TTR have been developed and the drug tafamidis is available as treatment.

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Proteostatic Hotspots in Amyloid Fibrils Protect Us from Neurodegeneration

Cited by 5 publications

References 10 publications

BRICHOS binds to a designed amyloid-forming β-protein and reduces proteasomal inhibition and aggresome formation

BRICHOS binds to a designed amyloid-forming β-protein and reduces proteasomal inhibition and aggresome formation

Bri2 BRICHOS client specificity and chaperone activity are governed by assembly state

Current and future treatment of amyloid diseases

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