O-GlcNAc Modification Protects against Protein Misfolding and Aggregation in Neurodegenerative Disease

2019 ◽  
Vol 10 (5) ◽  
pp. 2209-2221 ◽  
Author(s):  
Philip Ryan ◽  
Mingming Xu ◽  
Andrew K. Davey ◽  
Jonathan J. Danon ◽  
George D. Mellick ◽  
...  
Keyword(s):  
Neurodegenerative Disease ◽  
Protein Misfolding ◽  
Protein Misfolding And Aggregation

Detecting and Preventing Dehydration in Alzheimer's Patients: Multidisciplinary Approaches to Dementia Care

2017 ◽  
Vol 1 (1) ◽  
pp. 01-02
Author(s):  
Melina Oison
Keyword(s):  
Cognitive Impairment ◽  
Neurodegenerative Disease ◽  
Brain Atrophy ◽  
Protein Misfolding ◽  
Older Patients ◽  
Interstitial Fluid ◽  
Neuronal Dysfunction ◽  
Interstitial Fluid Volume ◽  
Protein Misfolding And Aggregation ◽  
The Relationship

Abnormalities of water homeostasis can be early expressions of neuronal dysfunction, brain atrophy, chronic cerebrovasculopathy and neurodegenerative disease. The aim of this study was to analyze the serum osmolality of subjects with cognitive impairment.The hydromolecular hypothesis intends to explain the relationship between dehydration and cognitive impairment in older patients as the result of protein misfolding and aggregation, in the presence of a low interstitial fluid volume, which is a defect of the microcirculation. Defective proteins were shown to impair the amount of information in brain biomolecular mechanisms, with consequent neuronal and synaptic damage.

scholarly journals Heat Shock Protein Grp78/BiP/HspA5 Binds Directly to TDP-43 and Mitigates Toxicity Associated with Neurodegenerative Disease Pathology

2021 ◽  
Author(s):  
Liberty François-Moutal ◽  
David Scott ◽  
Andrew Ambrose ◽  
Christopher Zerio ◽  
Kumara Dissanayake ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Neurodegenerative Disease ◽  
Protein Misfolding ◽  
Rna Binding ◽  
Proteotoxic Stress ◽  
Hsp70 Family ◽  
Protein Misfolding And Aggregation ◽  
Als Patients ◽  
The Relationship

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no cure or effective treatment in which TAR DNA Binding Protein of 43 kDa (TDP-43) abnormally accumulates into misfolded protein aggregates in affected neurons. It is widely accepted that protein misfolding and aggregation promote proteotoxic stress. The molecular chaperones are the body’s primary line of defense against proteotoxic stress and there has been long-standing interest in understanding the relationship between chaperones and aggregated protein in ALS. Of particular interest are the heat shock protein of 70 kDa (Hsp70) family of chaperones; however, defining which of the 13 human Hsp70 isoforms is critical for ALS, has presented many challenges. To gain insight into the specific Hsp70 that modulates TDP-43, we investigated the relationship between TDP-43 and the Hsp70s using proximity-dependent biotin identification (BioID) and discovered several Hsp70 isoforms associated with TDP-43 in the nucleus, raising the possibility of an interaction with native TDP-43. We further found that HspA5 bound specifically to the RNA-binding domain of TDP-43 using recombinantly expressed proteins. HspA5 is increased in prefrontal cortex neurons of ALS patients. Finally, overexpression of HspA5 in Drosophila rescued TDP-43-induced toxicity, suggesting that upregulation of HspA5 may have a compensatory role in ALS pathobiology.

scholarly journals The Pah-R261Q mouse reveals oxidative stress associated with amyloid-like hepatic aggregation of mutant phenylalanine hydroxylase

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Oscar Aubi ◽  
Karina S. Prestegård ◽  
Kunwar Jung-KC ◽  
Tie-Jun Sten Shi ◽  
Ming Ying ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Protein Misfolding ◽  
Phenylalanine Hydroxylase ◽  
Hepatic Tissue ◽  
Loss Of Function ◽  
Advantageous Position ◽  
Protein Misfolding And Aggregation ◽  
Activity Decrease ◽  
Systemic Accumulation ◽  
Altered Lipid

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.

scholarly journals Investigating the Disordered and Membrane-Active Peptide A-Cage-C Using Conformational Ensembles

Molecules ◽  
2021 ◽  
Vol 26 (12) ◽  
pp. 3607
Author(s):  
Olena Dobrovolska ◽  
Øyvind Strømland ◽  
Ørjan Sele Handegård ◽  
Martin Jakubec ◽  
Morten L. Govasli ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Protein Misfolding ◽  
Driving Forces ◽  
Conformational Space ◽  
Supported Bilayers ◽  
Conformational Ensembles ◽  
Protein Membrane ◽  
Chimeric Polypeptide ◽  
Protein Misfolding And Aggregation ◽  
In Silico Analyses

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.

scholarly journals The Non-Protein Amino Acid BMAA Is Misincorporated into Human Proteins in Place of l-Serine Causing Protein Misfolding and Aggregation

PLoS ONE ◽  
2013 ◽  
Vol 8 (9) ◽  
pp. e75376 ◽  
Author(s):  
Rachael Anne Dunlop ◽  
Paul Alan Cox ◽  
Sandra Anne Banack ◽  
Kenneth John Rodgers
Keyword(s):  
Amino Acid ◽  
Protein Misfolding ◽  
Protein Amino Acid ◽  
Human Proteins ◽  
Protein Misfolding And Aggregation

Glutamine repeats: structural hypotheses and neurodegeneration

2002 ◽  
Vol 30 (4) ◽  
pp. 548-551 ◽  
Author(s):  
L. Masino ◽  
A. Pastore
Keyword(s):  
Protein Misfolding ◽  
Trinucleotide Repeats ◽  
Intranuclear Inclusions ◽  
The Past ◽  
Cag Trinucleotide Repeats ◽  
Protein Misfolding And Aggregation ◽  
Polyglutamine Protein ◽  
Molecular Bases ◽  
Protein Models

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.

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