scholarly journals Molecular therapy targeting protein misfolding and aggregation for the polyglutamine diseases

2009 ◽  
Vol 49 (11) ◽  
pp. 913-916
Author(s):  
Yoshitaka Nagai
2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Oscar Aubi ◽  
Karina S. Prestegård ◽  
Kunwar Jung-KC ◽  
Tie-Jun Sten Shi ◽  
Ming Ying ◽  
...  

AbstractPhenylketonuria (PKU) is caused by autosomal recessive variants in phenylalanine hydroxylase (PAH), leading to systemic accumulation of L-phenylalanine (L-Phe) that may reach neurotoxic levels. A homozygous Pah-R261Q mouse, with a highly prevalent misfolding variant in humans, reveals the expected hepatic PAH activity decrease, systemic L-Phe increase, L-tyrosine and L-tryptophan decrease, and tetrahydrobiopterin-responsive hyperphenylalaninemia. Pah-R261Q mice also present unexpected traits, including altered lipid metabolism, reduction of liver tetrahydrobiopterin content, and a metabolic profile indicative of oxidative stress. Pah-R261Q hepatic tissue exhibits large ubiquitin-positive, amyloid-like oligomeric aggregates of mutant PAH that colocalize with selective autophagy markers. Together, these findings reveal that PKU, customarily considered a loss-of-function disorder, can also have toxic gain-of-function contribution from protein misfolding and aggregation. The proteostasis defect and concomitant oxidative stress may explain the prevalence of comorbid conditions in adult PKU patients, placing this mouse model in an advantageous position for the discovery of mutation-specific biomarkers and therapies.


Molecules ◽  
2021 ◽  
Vol 26 (12) ◽  
pp. 3607
Author(s):  
Olena Dobrovolska ◽  
Øyvind Strømland ◽  
Ørjan Sele Handegård ◽  
Martin Jakubec ◽  
Morten L. Govasli ◽  
...  

The driving forces and conformational pathways leading to amphitropic protein-membrane binding and in some cases also to protein misfolding and aggregation is the subject of intensive research. In this study, a chimeric polypeptide, A-Cage-C, derived from α-Lactalbumin is investigated with the aim of elucidating conformational changes promoting interaction with bilayers. From previous studies, it is known that A-Cage-C causes membrane leakages associated with the sporadic formation of amorphous aggregates on solid-supported bilayers. Here we express and purify double-labelled A-Cage-C and prepare partially deuterated bicelles as a membrane mimicking system. We investigate A-Cage-C in the presence and absence of these bicelles at non-binding (pH 7.0) and binding (pH 4.5) conditions. Using in silico analyses, NMR, conformational clustering, and Molecular Dynamics, we provide tentative insights into the conformations of bound and unbound A-Cage-C. The conformation of each state is dynamic and samples a large amount of overlapping conformational space. We identify one of the clusters as likely representing the binding conformation and conclude tentatively that the unfolding around the central W23 segment and its reorientation may be necessary for full intercalation at binding conditions (pH 4.5). We also see evidence for an overall elongation of A-Cage-C in the presence of model bilayers.


PLoS ONE ◽  
2013 ◽  
Vol 8 (9) ◽  
pp. e75376 ◽  
Author(s):  
Rachael Anne Dunlop ◽  
Paul Alan Cox ◽  
Sandra Anne Banack ◽  
Kenneth John Rodgers

2013 ◽  
Vol 10 (3) ◽  
pp. 440-446 ◽  
Author(s):  
H. Akiko Popiel ◽  
Toshihide Takeuchi ◽  
James R. Burke ◽  
Warren J. Strittmatter ◽  
Tatsushi Toda ◽  
...  

2002 ◽  
Vol 30 (4) ◽  
pp. 548-551 ◽  
Author(s):  
L. Masino ◽  
A. Pastore

A growing number of neurodegenerative diseases are caused by expansion of CAG trinucleotide repeats coding for polyglutamine. The presence of intranuclear inclusions in the affected neuronal cells has suggested a mechanism for pathogenesis based on protein misfolding and aggregation. Detailed understanding of these phenomena is therefore crucial in order to rationalize different phases of the diseases. In the past decade, a few studies have focused on the structural properties of polyglutamine and on the molecular bases of the aggregation process. Most of these studies have been performed on polyglutamine peptides and protein models. Only one report is currently available on the characterization of a full-length polyglutamine protein. The structural hypotheses resulting from these studies are reviewed here.


Author(s):  
Philip N. Hawkins

Amyloidosis is a disorder of protein folding in which normally soluble proteins are deposited in the interstitial space as insoluble and remarkably stable fibrils that progressively disrupt tissue structure and function of organs throughout the body. Protein misfolding and aggregation have increasingly been recognized in the pathogenesis of various other diseases, but amyloidosis—the disease directly caused by extracellular amyloid deposition—is a precise term with critical implications for patients with a specific group of life-threatening disorders. Amyloidosis may be acquired or hereditary and the pattern of organ involvement varies within and between types, though clinical phenotypes overlap greatly. Virtually any tissue other than the brain may be directly involved. Although histology remains the diagnostic gold standard, developments in scintigraphy and MRI technology often produce pathognomonic findings. Systemic amyloidosis is usually fatal, but the prognosis has improved as the result of increasingly effective treatments for many of the conditions that underlie it, notably the use of biologic anti-inflammatory agents in patients with AA amyloidosis and new immunomodulatory agents in patients with AL type. Better supportive care, including dialysis and solid organ transplantation, have also influenced the prognosis favourably. A range of specific novel therapies are currently in clinical development, including RNA inhibitors that suppress production of amyloid precursor proteins, drugs that promote their normal soluble conformation in the plasma, and immunotherapy approaches that directly target the amyloid deposits.


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