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.

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.

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.

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.

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.

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.

The importance of supportive periodontal therapy for molars treated with furcation tunnelling.

Background And Objective: Degree III furcation involvement (FI) represents a risk of molar tooth loss. A limited number of studies have assessed the survival of molars with degree III FI treated with tunnelling procedures.

Aims: The aim of the present study was to assess periodontal disease progression and tooth loss in a cohort of patients with degree III FI treated with tunnelling by two periodontists in a private practice setting in the UK and in a hospital setting in Sweden.

Recombinant production and purification of the human protein Tau.

Tau protein is a microtubule-stabilising protein whose aggregation is linked to Alzheimer's Disease and other forms of dementia. Tau biology is at the heart of cytoskeletal dynamics and neurodegenerative mechanisms, making it a crucial protein to study. Tau purification, however, is challenging as Tau is disordered, which makes it difficult to produce in recombinant system and is degradation-prone.

The furcation tunnel preparation-A prospective 5-year follow-up study.

Aim: The aim of this study was to prospectively follow furcation tunnelled molars over a 5-year period of supportive periodontal therapy (SPT) and to identify factors associated with tooth loss.

Materials And Methods: A total of 32 patients with 42 furcation tunnelled molars (all class III prior tunnelling) were recruited upon commencing SPT following active periodontal therapy. Clinical registrations, bacterial samples and standardised radiographs were taken at baseline, year 1 (no radiographs), 2 and 5.

MAP7 family proteins regulate kinesin-1 recruitment and activation.

Kinesin-1 is responsible for microtubule-based transport of numerous cellular cargoes. Here, we explored the regulation of kinesin-1 by MAP7 proteins. We found that all four mammalian MAP7 family members bind to kinesin-1.

The Hsp70-Hsp90 Chaperone Cascade in Protein Folding.

Conserved families of molecular chaperones assist protein folding in the cell. Here we review the conceptual advances on three major folding routes: (i) spontaneous, chaperone-independent folding; (ii) folding assisted by repetitive Hsp70 cycles; and (iii) folding by the Hsp70-Hsp90 cascades. These chaperones prepare their protein clients for folding on their own, without altering their folding path.

Dancing with the Diva: Hsp90-Client Interactions.

The molecular chaperone Hsp90 is involved in the folding, maturation, and degradation of a large number structurally and sequentially unrelated clients, often connected to serious diseases. Elucidating the principles of how Hsp90 recognizes this large variety of substrates is essential for comprehending the mechanism of this chaperone machinery, as well as it is a prerequisite for the design of client specific drugs targeting Hsp90. Here, we discuss the recent progress in understanding the substrate recognition principles of Hsp90 and its implications for the role of Hsp90 in the lifecycle of proteins.

Hsp90 Breaks the Deadlock of the Hsp70 Chaperone System.

Protein folding in the cell requires ATP-driven chaperone machines such as the conserved Hsp70 and Hsp90. It is enigmatic how these machines fold proteins. Here, we show that Hsp90 takes a key role in protein folding by breaking an Hsp70-inflicted folding block, empowering protein clients to fold on their own.

Picky Hsp90-Every Game with Another Mate.

In this issue of Molecular Cell, Sahasrabudhe et al. (2017) present a dramatically renovated functional cycle for the molecular chaperone Hsp90, which stimulates re-thinking of the mechanism of this vital protein folding machine.

Validation of a New System Using Tracheal Body Sound and Movement Data for Automated Apnea-Hypopnea Index Estimation.

Study Objectives: The current gold standard for assessment of obstructive sleep apnea is the in-laboratory polysomnography. This approach has high costs and inconveniences the patient, whereas alternative ambulatory systems are limited by reduced diagnostic abilities (type 4 monitors, 1 or 2 channels) or extensive setup (type 3 monitors, at least 4 channels). The current study therefore aims to validate a simplified automated type 4 monitoring system using tracheal body sound and movement data.

Apnea and heart rate detection from tracheal body sounds for the diagnosis of sleep-related breathing disorders.

Sleep apnea is one of the most common sleep disorders. Here, patients suffer from multiple breathing pauses longer than 10 s during the night which are referred to as apneas. The standard method for the diagnosis of sleep apnea is the attended cardiorespiratory polysomnography (PSG).

Production and purification of human Hsp90β in Escherichia coli.

The molecular chaperone Hsp90 is an essential member of the cellular proteostasis system. It plays an important role in the stabilisation and activation of a large number of client proteins and is involved in fatal disease processes, e.g.

Predictive blood plasma biomarkers for EGFR inhibitor-induced skin rash.

Epidermal growth factor receptor overexpression in human cancer can be effectively targeted by drugs acting as specific inhibitors of the receptor, like erlotinib, gefitinib, cetuximab and panitumumab. A common adverse effect is a typical papulopustular acneiform rash, whose occurrence and severity are positively correlated with overall survival in several cancer types. We studied molecules involved in epidermal growth factor receptor signaling which are quantifiable in plasma, with the aim of identifying biomarkers for the severity of rash.

Axin cancer mutants form nanoaggregates to rewire the Wnt signaling network.

Signaling cascades depend on scaffold proteins that regulate the assembly of multiprotein complexes. Missense mutations in scaffold proteins are frequent in human cancer, but their relevance and mode of action are poorly understood. Here we show that cancer point mutations in the scaffold protein Axin derail Wnt signaling and promote tumor growth in vivo through a gain-of-function mechanism.