Protein-Remodeling Factors As Potential Therapeutics for Neurodegenerative Disease

Protein misfolding is implicated in numerous neurodegenerative disorders including amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, and Huntington's disease. A unifying feature of patients with these disorders is the accumulation of deposits comprised of misfolded protein. Aberrant protein folding can cause toxicity through a loss or gain of protein function, or both. An intriguing therapeutic approach to counter these disorders is the application of protein-remodeling factors to resolve these misfolded conformers and return the proteins to their native fold and function. Here, we describe the application of protein-remodeling factors to alleviate protein misfolding in neurodegenerative disease. We focus on Hsp104, Hsp110/Hsp70/Hsp40, NMNAT, and HtrA1, which can prevent and reverse protein aggregation. While many of these protein-remodeling systems are highly promising, their activity can be limited. Thus, engineering protein-remodeling factors to enhance their activity could be therapeutically valuable. Indeed, engineered Hsp104 variants suppress neurodegeneration in animal models, which opens the way to novel therapeutics and mechanistic probes to help understand neurodegenerative disease

Retreating to nature : rethinking 'therapeutic landscapes'

There is a long history of removing oneself from ‘society’ in order to recuperate or repair. This paper considers a yoga and massage retreat in Southern Spain, and what opportunities this retreat experience might offer for recuperation and the creation of healthy bodies. The paper positions ‘nature’ as an active participant, and as ‘enrolled’ in the experiences of the retreat as a ‘therapeutic landscape’, and questions how and what particular aspects of yoga practice (in intimate relation with place) give rise to therapeutic experiences

Drag of suction cup tags on swimming animals : modeling and measurement

© The Author(s), 2013. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Marine Mammal Science 30 (2014): 726–746, doi:10.1111/mms.12083.Bio-logging tags are widely used to study the behavior and movements of marine mammals with the tacit assumption of little impact to the animal. However, tags on fast-swimming animals generate substantial hydrodynamic forces potentially affecting behavior and energetics adversely, or promoting early removal of the tag. In this work, hydrodynamic loading of three novel tag housing designs are compared over a range of swimming speeds using computational fluid dynamics (CFD). Results from CFD simulation were verified using tag models in a water flume with close agreement. Drag forces were reduced by minimizing geometric disruptions to the flow around the housing, while lift forces were reduced by minimizing the frontal cross-sectional area of the housing and holding the tag close to the attachment surface. Hydrodynamic tag design resulted in an experimentally measured 60% drag force reduction in 5.6 m/s flow. For all housing designs, off-axis flow increased the magnitude of the force on the tag. Experimental work with a common dolphin (Delphinus delphis) cadaver indicates that the suction cups used to attach the types of tags described here provide sufficient attachment force to resist failure to predicted forces at swimming speeds of up to 10 m/s.This work was supported by NOPP with NSF funds through ONR Grant N00014-11-1- 0113. MJ was supported by NOPP and the MASTS pooling initiative (The Marine Alliance for Science and Technology for Scotland)

Tracing Spasmodic Dysphonia: the source of Ludwig Traube’s priority

Objectives: Since the mid-20th century, one citation is given historical priority as the first description of Spasmodic Dysphonia (SD): Ludwig Traube’s 1871 case of the “spastic form of nervous hoarseness”. Our objective is to understand how this case serves as the foundation of understanding laryngeal movement disorders. Methods: The original German paper was located and translated. Bibliographical and bibliometric methods are used to determine the citation history of this original source over the past 140 years. Results: Although secondary citations in contemporary publications typically credit Traube for establishing the clinical entity SD, his case does not conform to currently accepted diagnostic features. Citation patterns indicate the source of Traube’s priority is publications by Arnold and Luchsinger, mid-20th century ENT clinician, particularly their influential 1965 textbook used to train US and UK clinicians on voice disorders for several generations. Conclusions: Sometimes secondary citations in medical literature lead to the inadvertent perpetuation of factual misrepresentation. The clinical picture of Traube’s original case does not represent what clinicians would recognize as SD today. The rich 19th century literature on voice disorders is a valuable resource for present day clinicians

Soluble oligomers are sufficient for transmission of a yeast prion but do not confer phenotype

Amyloidogenic proteins aggregate through a self-templating mechanism that likely involves oligomeric or prefibrillar intermediates. For disease-associated amyloidogenic proteins, such intermediates have been suggested to be the primary cause of cellular toxicity. However, isolation and characterization of these oligomeric intermediates has proven difficult, sparking controversy over their biological relevance in disease pathology. Here, we describe an oligomeric species of a yeast prion protein in cells that is sufficient for prion transmission and infectivity. These oligomers differ from the classic prion aggregates in that they are soluble and less resistant to SDS. We found that large, SDS-resistant aggregates were required for the prion phenotype but that soluble, more SDS-sensitive oligomers contained all the information necessary to transmit the prion conformation. Thus, we identified distinct functional requirements of two types of prion species for this endogenous epigenetic element. Furthermore, the nontoxic, self-replicating amyloid conformers of yeast prion proteins have again provided valuable insight into the mechanisms of amyloid formation and propagation in cells

Mining Disaggregase Sequence Space to Safely Counter TDP-43, FUS, and α-Synuclein Proteotoxicity.

Hsp104 is an AAA+ protein disaggregase, which can be potentiated via diverse mutations in its autoregulatory middle domain (MD) to mitigate toxic misfolding of TDP-43, FUS, and α-synuclein implicated in fatal neurodegenerative disorders. Problematically, potentiated MD variants can exhibit off-target toxicity. Here, we mine disaggregase sequence space to safely enhance Hsp104 activity via single mutations in nucleotide-binding domain 1 (NBD1) or NBD2. Like MD variants, NBD variants counter TDP-43, FUS, and α-synuclein toxicity and exhibit elevated ATPase and disaggregase activity. Unlike MD variants, non-toxic NBD1 and NBD2 variants emerge that rescue TDP-43, FUS, and α-synuclein toxicity. Potentiating substitutions alter NBD1 residues that contact ATP, ATP-binding residues, or the MD. Mutating the NBD2 protomer interface can also safely ameliorate Hsp104. Thus, we disambiguate allosteric regulation of Hsp104 by several tunable structural contacts, which can be engineered to spawn enhanced therapeutic disaggregases with minimal off-target toxicity

A hisztériával kapcsolatos diskurzusok tanulságai a szomatizációs jelenségek és a betegségmagatartás megértéséhez = The relevance of discourses about hysteria in the understanding of somatization phenomena and illness behaviour

Napjainkban a magatartástudományok képviselőinek egyszerre kell számolniuk a betegségekkel kapcsolatos bizonyosság és tudás konfliktusait előhívó medikalizációs-technicizációs orvostudományi tendenciákkal és a társadalomtudományok ezekre reflektáló, kritikai és „posztmodern” megközelítéseivel. Ebből adódóan igen fontos kihívásként jelentkezik az interdiszciplináris megközelítés szükségessége. Különösen így van ez a nehezen definiálható betegségek - a szomatizációs és pszichoszomatikus zavarok - esetében, ahol a betegségmagatartás gyakorlati problémái, továbbá a tünetek, a diagnózisok és a szenvedés „valódiságának” episztemológiai kérdései egyszerre vannak jelen. Az utóbbi másfél évtized kritikai társadalomtudományi kutatásaiban rendkívüli figyelmet kapott a szomatizációs zavarok és a klasszikus pszichoszomatikus kórképek elődjének számító hisztéria kérdésköre. A tanulmány a szakmai és laikus szóhasználatban nem hivatalosan máig tovább élő betegséggel kapcsolatos társadalomtudományi és orvosi megközelítések közül azokat mutatja be, amelyek szempontokkal szolgálhatnak a szomatizációs és pszichoszomatikus kórképek, valamint a velük kapcsolatos érzelmi és viselkedéses reakciók elemzéséhez és megértéséhez

Functional Amyloid Formation within Mammalian Tissue

Amyloid is a generally insoluble, fibrous cross-β sheet protein aggregate. The process of amyloidogenesis is associated with a variety of neurodegenerative diseases including Alzheimer, Parkinson, and Huntington disease. We report the discovery of an unprecedented functional mammalian amyloid structure generated by the protein Pmel17. This discovery demonstrates that amyloid is a fundamental nonpathological protein fold utilized by organisms from bacteria to humans. We have found that Pmel17 amyloid templates and accelerates the covalent polymerization of reactive small molecules into melanin—a critically important biopolymer that protects against a broad range of cytotoxic insults including UV and oxidative damage. Pmel17 amyloid also appears to play a role in mitigating the toxicity associated with melanin formation by sequestering and minimizing diffusion of highly reactive, toxic melanin precursors out of the melanosome. Intracellular Pmel17 amyloidogenesis is carefully orchestrated by the secretory pathway, utilizing membrane sequestration and proteolytic steps to protect the cell from amyloid and amyloidogenic intermediates that can be toxic. While functional and pathological amyloid share similar structural features, critical differences in packaging and kinetics of assembly enable the usage of Pmel17 amyloid for normal function. The discovery of native Pmel17 amyloid in mammals provides key insight into the molecular basis of both melanin formation and amyloid pathology, and demonstrates that native amyloid (amyloidin) may be an ancient, evolutionarily conserved protein quaternary structure underpinning diverse pathways contributing to normal cell and tissue physiology

Evaluation of nitrogen dioxide chemiluminescence monitors in a polluted urban environment

International audienceData from a recent field campaign in Mexico City are used to evaluate the performance of the EPA Federal Reference Method for monitoring the ambient concentrations of NO2. Measurements of NO2 from standard chemiluminescence monitors equipped with molybdenum oxide converters are compared with those from Tunable Infrared Laser Differential Absorption Spectroscopy (TILDAS) and Differential Optical Absorption Spectroscopy (DOAS) instruments. A significant interference in the chemiluminescence measurement is shown to account for up to 50% of ambient NO2 concentration during afternoon hours. As expected, this interference correlates well with non-NOx reactive nitrogen species (NOz) as well as with ambient O3 concentrations, indicating a photochemical source for the interfering species. A combination of ambient gas phase nitric acid and alkyl and multifunctional alkyl nitrates is deduced to be the primary cause of the interference. Observations at four locations at varying proximities to emission sources indicate that the percentage contribution of HNO3 to the interference decreases with time as the air parcel ages. Alkyl and multifunctional alkyl nitrate concentrations are calculated to reach concentrations as high as several ppb inside the city, on par with the highest values previously observed in other urban locations. Averaged over the MCMA-2003 field campaign, the chemiluminescence monitor interference resulted in an average measured NO2 concentration up to 22% greater than that from co-located spectroscopic measurements. Thus, this interference has the potential to initiate regulatory action in areas that are close to non-attainment and may mislead atmospheric photochemical models used to assess control strategies for photochemical oxidants