scholarly journals Cystic fibrosis – a multiorgan protein misfolding disease

2015 ◽  
Vol 1 (2) ◽  
Author(s):  
Douglas Fraser-Pitt ◽  
Deborah O’Neil
Keyword(s):  
Cystic Fibrosis ◽  
Protein Misfolding ◽  
Misfolding Disease

scholarly journals Type 2 diabetes as a protein misfolding disease

2015 ◽  
Vol 21 (7) ◽  
pp. 439-449 ◽  
Author(s):  
Abhisek Mukherjee ◽  
Diego Morales-Scheihing ◽  
Peter C. Butler ◽  
Claudio Soto
Keyword(s):  
Type 2 Diabetes ◽  
Protein Misfolding ◽  
Misfolding Disease

scholarly journals Biological and Structural Basis for Aha1 Regulation of Hsp90 ATPase Activity in Maintaining Proteostasis in the Human Disease Cystic Fibrosis

2010 ◽  
Vol 21 (6) ◽  
pp. 871-884 ◽  
Author(s):  
Atanas V. Koulov ◽  
Paul LaPointe ◽  
Bingwen Lu ◽  
Abbas Razvi ◽  
Judith Coppinger ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Atpase Activity ◽  
Protein Misfolding ◽  
Atp Hydrolysis ◽  
Structural Basis ◽  
Inherited Disease ◽  
Hsp90 Chaperone ◽  
Terminal Domains

The activator of Hsp90 ATPase 1, Aha1, has been shown to participate in the Hsp90 chaperone cycle by stimulating the low intrinsic ATPase activity of Hsp90. To elucidate the structural basis for ATPase stimulation of human Hsp90 by human Aha1, we have developed novel mass spectrometry approaches that demonstrate that the N- and C-terminal domains of Aha1 cooperatively bind across the dimer interface of Hsp90 to modulate the ATP hydrolysis cycle and client activity in vivo. Mutations in both the N- and C-terminal domains of Aha1 impair its ability to bind Hsp90 and stimulate its ATPase activity in vitro and impair in vivo the ability of the Hsp90 system to modulate the folding and trafficking of wild-type and variant (ΔF508) cystic fibrosis transmembrane conductance regulator (CFTR) responsible for the inherited disease cystic fibrosis (CF). We now propose a general model for the role of Aha1 in the Hsp90 ATPase cycle in proteostasis whereby Aha1 regulates the dwell time of Hsp90 with client. We suggest that Aha1 activity integrates chaperone function with client folding energetics by modulating ATPase sensitive N-terminal dimer structural transitions, thereby protecting transient folding intermediates in vivo that could contribute to protein misfolding systems disorders such as CF when destabilized.

scholarly journals Distinct proteostasis states drive pharmacologic chaperone susceptibility for Cystic Fibrosis Transmembrane Conductance Regulator misfolding mutants

2021 ◽  
Author(s):  
Eli Fritz McDonald ◽  
Carleen Mae P. Sabusap ◽  
Minsoo Kim ◽  
Lars Plate
Keyword(s):  
Cystic Fibrosis ◽  
Protein Misfolding ◽  
Clinical Success ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Pharmacological Chaperone ◽  
Pharmacological Chaperones ◽  
Misfolding Diseases ◽  
The Impact ◽  
Cystic Fibrosis Transmembrane

ABSTRACTPharmacological chaperones represent a class of therapeutic compounds for treating protein misfolding diseases. One of the most prominent examples is the FDA-approved pharmacological chaperone lumacaftor (VX-809), which has transformed cystic fibrosis (CF) therapy. CF is a fatal disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). VX-809 corrects folding of F508del CFTR, the most common patient mutation, yet F508del exhibits only mild VX-809 response. In contrast, rarer mutations P67L and L206W are hyper-responsive to VX-809, while G85E is non-responsive. Despite the clinical success of VX-809, the mechanistic origin for the distinct susceptibility of mutants remains unclear. Here, we use interactomics to characterize the impact of VX-809 on proteostasis interactions of P67L and L206W and compare these to F508del and G85E. We determine hyper-responsive mutations P67L and L206W exhibit decreased interactions with proteasomal, and autophagy degradation machinery compared to F508del and G85E. We then show inhibiting the proteasome attenuates P67L and L206W VX-809 response, and inhibiting the lysosome attenuates F508del VX-809 response. Our data suggests a previously unidentified but required role for protein degradation in VX-809 correction. Furthermore, we present an approach for identifying proteostasis characteristics of mutant-specific therapeutic response to pharmacological chaperones.

Recent Studies on Design and Development of Drugs Against Alzheimer’s Disease (AD) Based on Inhibition of BACE-1 and Other AD-causative Agents

2020 ◽  
Vol 20 (13) ◽  
pp. 1195-1213 ◽  
Author(s):  
Satya P. Gupta ◽  
Vaishali M. Patil
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Protein ◽  
Protein Misfolding ◽  
Inhibition Mechanism ◽  
Design And Development ◽  
Causative Agents ◽  
Misfolding Disease ◽  
Structural Aspects

Background: Alzheimer’s disease (AD) is one of the neurodegenerative diseases and has been hypothesized to be a protein misfolding disease. In the generation of AD, β-secretase, γ-secretase, and tau protein play an important role. A literature search reflects ever increasing interest in the design and development of anti-AD drugs targeting β-secretase, γ-secretase, and tau protein. Objective: The objective is to explore the structural aspects and role of β-secretase, γ-secretase, and tau protein in AD and the efforts made to exploit them for the design of effective anti-AD drugs. Methods: The manuscript covers the recent studies on design and development of anti-AD drugs exploiting amyloid and cholinergic hypotheses. Results: Based on amyloid and cholinergic hypotheses, effective anti-AD drugs have been searched out in which non-peptidic BACE1 inhibitors have been most prominent. Conclusion: Further exploitation of the structural aspects and the inhibition mechanism for β-secretase, γ-secretase, and tau protein and the use of cholinergic hypothesis may lead still more potent anti-AD drugs.

Atherosclerosis: another protein misfolding disease?

2002 ◽  
Vol 8 (8) ◽  
pp. 370-374 ◽  
Author(s):  
Fulvio Ursini ◽  
Kelvin J.A Davies ◽  
Matilde Maiorino ◽  
Tiziana Parasassi ◽  
Alex Sevanian
Keyword(s):  
Protein Misfolding ◽  
Misfolding Disease

scholarly journals The Role of Activity in Synaptic Degeneration in a Protein Misfolding Disease, Prion Disease

PLoS ONE ◽  
2012 ◽  
Vol 7 (7) ◽  
pp. e41182 ◽  
Author(s):  
Matteo Caleo ◽  
Laura Restani ◽  
Eleonora Vannini ◽  
Zuzana Siskova ◽  
Hussain Al-Malki ◽  
...  
Keyword(s):  
Prion Disease ◽  
Protein Misfolding ◽  
Synaptic Degeneration ◽  
Misfolding Disease

GCK-MODY diabetes as a protein misfolding disease: The mutation R275C promotes protein misfolding, self-association and cellular degradation

2014 ◽  
Vol 382 (1) ◽  
pp. 55-65 ◽  
Author(s):  
Maria Negahdar ◽  
Ingvild Aukrust ◽  
Janne Molnes ◽  
Marie H. Solheim ◽  
Bente B. Johansson ◽  
...  
Keyword(s):  
Protein Misfolding ◽  
Self Association ◽  
Misfolding Disease

scholarly journals Immunoglobulin light chain amyloid aggregation

2018 ◽  
Vol 54 (76) ◽  
pp. 10664-10674 ◽  
Author(s):  
Luis M. Blancas-Mejia ◽  
Pinaki Misra ◽  
Christopher J. Dick ◽  
Shawna A. Cooper ◽  
Keely R. Redhage ◽  
...  
Keyword(s):  
Light Chain ◽  
Protein Misfolding ◽  
Al Amyloidosis ◽  
Amyloid Aggregation ◽  
Immunoglobulin Light Chain ◽  
Misfolding Disease

Light chain (AL) amyloidosis is a devastating, complex, and incurable protein misfolding disease.

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