A Peptide Strategy for Inhibiting Different Protein Aggregation Pathways.

Protein aggregation correlates with many human diseases. Protein aggregates differ in structure and shape. Strategies to develop effective aggregation inhibitors that reach the clinic failed so far.

Somatic CAG Repeat Stability in a Transgenic Sheep Model of Huntington's Disease.

Somatic instability of the huntingtin (HTT) CAG repeat mutation modifies age-at-onset of Huntington's disease (HD). Understanding the mechanism and pathogenic consequences of instability may reveal therapeutic targets. Using small-pool PCR we analyzed CAG instability in the OVT73 sheep model which expresses a full-length human cDNA HTT transgene.

How do protein aggregates escape quality control in neurodegeneration?

Protein aggregates are hallmarks of neurodegenerative diseases. The protein quality control (PQC) system normally prevents proteins from misfolding and accumulation; however, proteins somehow escape this control on disease. Here we review advances in the role of PQC in protein aggregation and neurodegeneration.

Molecular Strategies to Target Protein Aggregation in Huntington's Disease.

Huntington's disease (HD) is a neurodegenerative disorder caused by the aggregation of the mutant huntingtin (mHTT) protein in nerve cells. mHTT self-aggregates to form soluble oligomers and insoluble fibrils, which interfere in a number of key cellular functions. This leads to cell quiescence and ultimately cell death.

Extensive Anti-CoA Immunostaining in Alzheimer's Disease and Covalent Modification of Tau by a Key Cellular Metabolite Coenzyme A.

Alzheimer's disease (AD) is a neurodegenerative disorder, accounting for at least two-thirds of dementia cases. A combination of genetic, epigenetic and environmental triggers is widely accepted to be responsible for the onset and development of AD. Accumulating evidence shows that oxidative stress and dysregulation of energy metabolism play an important role in AD pathogenesis, leading to neuronal dysfunction and death.

Periodontal furcation lesions: A survey of diagnosis and management by general dental practitioners.

Aim: The aim of this study was to explore general dental practitioners' (GDPs) attitude to periodontal furcation involvement (FI).

Materials And Methods: An online survey focused on diagnosis and management of periodontal FI was circulated to GDPs in seven different countries.

Results: A total of 400 responses were collected.

A Multi-Omic Huntington's Disease Transgenic Sheep-Model Database for Investigating Disease Pathogenesis.

Background: The pathological mechanism of cellular dysfunction and death in Huntington's disease (HD) is not well defined. Our transgenic HD sheep model (OVT73) was generated to investigate these mechanisms and for therapeutic testing. One particular cohort of animals has undergone focused investigation resulting in a large interrelated multi-omic dataset, with statistically significant changes observed comparing OVT73 and control 'omic' profiles and reported in literature.

Predicting the SARS-CoV-2 effective reproduction number using bulk contact data from mobile phones.

Over the last months, cases of SARS-CoV-2 surged repeatedly in many countries but could often be controlled with nonpharmaceutical interventions including social distancing. We analyzed deidentified Global Positioning System (GPS) tracking data from 1.15 to 1.

Castration delays epigenetic aging and feminizes DNA methylation at androgen-regulated loci.

In mammals, females generally live longer than males. Nevertheless, the mechanisms underpinning sex-dependent longevity are currently unclear. Epigenetic clocks are powerful biological biomarkers capable of precisely estimating chronological age and identifying novel factors influencing the aging rate using only DNA methylation data.

The Mitochondrial Hsp90 TRAP1 and Alzheimer's Disease.

Alzheimer's Disease (AD) is the most common form of dementia, characterised by intra- and extracellular protein aggregation. In AD, the cellular protein quality control (PQC) system is derailed and fails to prevent the formation of these aggregates. Especially the mitochondrial paralogue of the conserved Hsp90 chaperone class, tumour necrosis factor receptor-associated protein 1 (TRAP1), is strongly downregulated in AD, more than other major PQC factors.

Approximal plaque pH lowering after sugar intake in a periodontally infected dentition.

Objectives: The aim of this study was to evaluate the effect of periodontal inflammation on the approximal plaque pH after a sucrose rinse.

Materials And Methods: Thirty-two periodontitis patients (aged 38-72 years; 9M/23F) were included. All patients were in need of periodontal surgery.

Double J-domain piloting of an Hsp70 substrate.

Heat shock 70 kDa protein (Hsp70) chaperones play a crucial role in the biogenesis of tail-anchored proteins (TAs), starting a downstream cascade to the endoplasmic reticulum (ER) via the guided-entry-of-tail-anchored protein (GET) pathway. J-domain proteins (JDPs) are generally known to assist Hsp70s, but their specific role in TA targeting remains unclear. Cho et al.

Alzheimer Cells on Their Way to Derailment Show Selective Changes in Protein Quality Control Network.

Alzheimer's Disease is driven by protein aggregation and is characterized by accumulation of Tau protein into neurofibrillary tangles. In healthy neurons the cellular protein quality control is successfully in charge of protein folding, which raises the question to which extent this control is disturbed in disease. Here, we describe that brain cells in Alzheimer's Disease show very specific derailment of the protein quality control network.

The Hsp70-Hsp90 co-chaperone Hop/Stip1 shifts the proteostatic balance from folding towards degradation.

Hop/Stip1/Sti1 is thought to be essential as a co-chaperone to facilitate substrate transfer between the Hsp70 and Hsp90 molecular chaperones. Despite this proposed key function for protein folding and maturation, it is not essential in a number of eukaryotes and bacteria lack an ortholog. We set out to identify and to characterize its eukaryote-specific function.

Impact of embryo culture and transfer on blood pressure regulation in the adolescent lamb.

Nutrition during the periconceptional period influences postnatal cardiovascular health. We determined whether in vitro embryo culture and transfer, which are manipulations of the nutritional environment during the periconceptional period, dysregulate postnatal blood pressure and blood pressure regulatory mechanisms. Embryos were either transferred to an intermediate recipient ewe (ET) or cultured in vitro in the absence (IVC) or presence of human serum (IVCHS) and a methyl donor (IVCHS+M) for 6 days.

DNA methylation study of Huntington's disease and motor progression in patients and in animal models.

Although Huntington's disease (HD) is a well studied Mendelian genetic disorder, less is known about its associated epigenetic changes. Here, we characterize DNA methylation levels in six different tissues from 3 species: a mouse huntingtin (Htt) gene knock-in model, a transgenic HTT sheep model, and humans. Our epigenome-wide association study (EWAS) of human blood reveals that HD mutation status is significantly (p < 10) associated with 33 CpG sites, including the HTT gene (p = 6.

Circuit-Specific Dendritic Development in the Piriform Cortex.

Dendritic geometry is largely determined during postnatal development and has a substantial impact on neural function. In sensory processing, postnatal development of the dendritic tree is affected by two dominant circuit motifs, ascending sensory feedforward inputs and descending and local recurrent connections. In the three-layered anterior piriform cortex (aPCx), neurons in the sublayers 2a and 2b display vertical segregation of these two circuit motifs.

Auditory event-related potentials in individuals with subjective and mild cognitive impairment.

Objective: The analysis of event-related potentials (ERPs) is a useful tool to differentiate between healthy older adults, and individuals with mild cognitive impairment (MCI). Less is known about the ERPs' sensitivity of differentiating between individuals with subjective cognitive impairment (SCI) and MCI, as early evidence indicates similar brain alterations between these two groups. In order, to establish tests that are sensitive to subclinical impairment, this study compared auditory evoked ERPs between individuals with SCI and MCI.

Behind closed gates - chaperones and charged residues determine protein fate.

Charged residues flanking aggregation-prone regions play a role in protein folding and prevention of aggregation. In this issue of The EMBO Journal, Houben et al exploit the role of such charged gatekeepers in aggregation suppression and find that negative charges are more effective than positive ones. Strikingly, the prominent Hsp70 chaperone has a strong preference for the less effective, basic gate keepers.

Epidemics with mutating infectivity on small-world networks.

Epidemics and evolution of many pathogens occur on similar timescales so that their dynamics are often entangled. Here, in a first step to study this problem theoretically, we analyze mutating pathogens spreading on simple SIR networks with grid-like connectivity. We have in mind the spatial aspect of epidemics, which often advance on transport links between hosts or groups of hosts such as cities or countries.

The mechanism of Hsp90-induced oligomerizaton of Tau.

Aggregation of the microtubule-associated protein Tau is a hallmark of Alzheimer's disease with Tau oligomers suspected as the most toxic agent. Tau is a client of the molecular chaperone Hsp90, although it is unclear whether and how the chaperone massages the structure of intrinsically disordered Tau. Using electron paramagnetic resonance, we extract structural information from the very broad conformational ensemble of Tau: Tau in solution is highly dynamic and polymorphic, although "paper clip"-shaped by long-range contacts.

Arginine π-stacking drives binding to fibrils of the Alzheimer protein Tau.

Aggregation of the Tau protein into fibrils defines progression of neurodegenerative diseases, including Alzheimer's Disease. The molecular basis for potentially toxic reactions of Tau aggregates is poorly understood. Here we show that π-stacking by Arginine side-chains drives protein binding to Tau fibrils.

Regulation of α-synuclein by chaperones in mammalian cells.

Neurodegeneration in patients with Parkinson's disease is correlated with the occurrence of Lewy bodies-intracellular inclusions that contain aggregates of the intrinsically disordered protein α-synuclein. The aggregation propensity of α-synuclein in cells is modulated by specific factors that include post-translational modifications, Abelson-kinase-mediated phosphorylation and interactions with intracellular machineries such as molecular chaperones, although the underlying mechanisms are unclear. Here we systematically characterize the interaction of molecular chaperones with α-synuclein in vitro as well as in cells at the atomic level.