A5011828447- Prion Diseases and Protein Misfolding
- Alzheimer's disease research and treatments
- Neurological diseases and metabolism
- Trace Elements in Health
- Dementia and Cognitive Impairment Research
- RNA regulation and disease
- Endoplasmic Reticulum Stress and Disease
- Parkinson's Disease Mechanisms and Treatments
- Enzyme Structure and Function
- Infectious Encephalopathies and Encephalitis
- Amino Acid Enzymes and Metabolism
- Connexins and lens biology
- Alcoholism and Thiamine Deficiency
- RNA Research and Splicing
- Agriculture, Soil, Plant Science
- Metallurgy and Material Science
- S100 Proteins and Annexins
- Cellular transport and secretion
- Molten salt chemistry and electrochemical processes
- Primary Care and Health Outcomes
- Memory and Neural Mechanisms
- Nuclear Physics and Applications
- Catalytic Processes in Materials Science
- Lipid metabolism and disorders
- Neuroscience and Neuropharmacology Research
Case Western Reserve University
2015-2025
University School
2019-2025
Duke University
2023
Western University of Health Sciences
2023
Cornell University
2022-2023
National Institute of Allergy and Infectious Diseases
2013-2021
National Institutes of Health
2013-2021
Rocky Mountain Research (United States)
2018-2020
University of Alberta
2010-2018
Global Viral
2014-2015
Little is known about the structural basis of prion strains. Here we provide a high (3.0 Å) resolution cryo-electron microscopy-based structure infectious brain-derived fibrils mouse anchorless RML scrapie strain which, like recently determined hamster 263K strain, has parallel in-register β-sheet-based core. Several motifs are shared between these ex vivo strains, including an amino-proximal steric zipper and three β-arches. However, detailed comparisons reveal variations in topologies...
Structures of the infectious form prion protein (e.g. PrP(Sc) or PrP-Scrapie) remain poorly defined. The prevalent structural models retain most native α-helices normal, noninfectious protein, cellular (PrP(C)), but evidence is accumulating that these helices are absent in amyloid. Moreover, recombinant PrP(C) can amyloid fibrils vitro have parallel in-register intermolecular β-sheet architectures domains originally occupied by 2 and 3. Here, we provide solid-state NMR latter also true...
Alzheimer disease (AD) and chronic traumatic encephalopathy (CTE) involve the abnormal accumulation in brain of filaments composed both three-repeat (3R) four-repeat (4R) (3R/4R) tau isoforms. To probe molecular basis for AD's filament propagation to improve detection aggregates as potential biomarkers, we have exploited seeded polymerization growth mechanism develop a highly selective ultrasensitive cell-free seed amplification assay optimized AD (AD real-time quaking-induced conversion or...
Prion disease is a fatal, incurable neurodegenerative of humans and other mammals caused by conversion cellular prion protein (PrPC) into self-propagating neurotoxic conformer (prions; PrPSc). Strong genetic proofs concept support lowering PrP expression as therapeutic strategy. Antisense oligonucleotides (ASOs) can provide practical route to 1 target mRNA in the brain, but their development for has been hindered 3 unresolved issues from prior work: uncertainty about mechanism action,...
Multiple neurodegenerative diseases are characterized by aggregation of tau molecules. Adult humans express six isoforms that contain either 3 or 4 microtubule binding repeats (3R 4R tau). Different involve preferential 3R (e.g Pick disease), (e.g. progressive supranuclear palsy), both and molecules [e.g. Alzheimer disease chronic traumatic encephalopathy]. Three ultrasensitive cell-free seed amplification assays [called real-time quaking induced conversion (tau RT-QuIC) assays] have been...
Prion strains in a given type of mammalian host are distinguished by differences clinical presentation, neuropathological lesions, survival time, and characteristics the infecting prion protein (PrP) assemblies. Near-atomic structures prions from two species with different PrP sequences have been determined but comparisons distinct same amino acid sequence needed to identify purely conformational determinants strain characteristics. Here we report 3.2 Å resolution cryogenic electron...
Tau neurofibrillary tangles (NFTs) in the presence of amyloid-β (Aβ) plaques are required for diagnosis Alzheimer's Disease (AD) and closely track with cognitive impairment, yet cognitively normal aged individuals frequently exhibit NFTs arising from tau seed accumulation. This may suggest that not all species equally pathogenic raises question whether unidentified modifications augment seeding activity neurodegeneration AD. We investigated how biochemical relate to clinicopathological...
Hypochlorous acid (HOCl) is produced naturally by neutrophils and other cells to kill conventional microbes in vivo. Synthetic preparations containing HOCl can also be effective as microbial disinfectants. Here we have tested whether inactivate prions self-propagating protein amyloid seeds. Prions are deadly pathogens that notoriously difficult inactivate, standard disinfection protocols often inadequate. Recommended treatments for prion decontamination include strongly basic (pH ≥~12)...
Rapid and sensitive detection of prions is important in managing prion diseases. The real-time quaking-induced conversion (RT-QuIC) assay for seeding activity has been applied to many diseases provides specific antemortem diagnostic testing. We evaluated RT-QuIC's long-term consistency varied multiple reaction parameters. Repeated assays a single scrapie sample using plate readers recombinant protein (rPrP(Sen)) substrates gave comparable results. N-terminal truncated hamster rPrP(Sen)...
Recent work with prion diseases and synucleinopathies indicates that accurate diagnostic methods for protein-folding can be based on the ultrasensitive, amplified measurement of pathological aggregates in biospecimens. A better understanding physicochemical factors control seeded polymerization such aggregates, their amplification vitro, should allow improvements existing assay platforms, as well development new assays other proteopathic aggregates. Here, we systematically investigated...
Calnexin is a molecular chaperone and component of the quality control secretory pathway. We have generated calnexin gene-deficient mice (cnx(-/-)) showed that deficiency leads to myelinopathy. Calnexin-deficient were viable with no discernible effects on other systems, including immune function, instead they demonstrated dysmyelination as documented by reduced conductive velocity nerve fibers electron microscopy analysis sciatic spinal cord. Myelin peripheral central nervous systems...
ABSTRACT Classical mammalian prions are assemblies of prion protein molecules that extraordinarily transmissible, with a microgram containing up to 10 8 lethal doses infectivity 1,2 . Unlike most other pathologic and amyloidogenic proteins, typically contain glycolipid anchors 3 abundant asparagine‐linked glycans 4‐6 The infectious nature, complexity, biophysical properties have complicated structural analyses stymied any prior elucidation 3D conformation at the polypeptide backbone level 7...
Tau neurofibrillary tangles are a hallmark of Alzheimer's disease neuropathological change. However, it remains largely unclear how distinctive tau seeds (i.e. 3R/4R) correlate with histological indicators accumulation. Furthermore, AD co-pathology is thought to influence features and progression other neurodegenerative diseases including Lewy body disease; yet measurements different types in the setting such an unmet need. Here, we use real-time quaking-induced conversion (RT-QuIC) assays...
<h3>PURPOSE</h3> The paradox of primary care is the observation that associated with apparently low levels evidence-based for individual diseases, but systems based on have healthier populations, use fewer resources, and less health inequality. purpose this article to explore, from a complex perspective, mechanisms might account effects beyond disease-specific care. <h3>METHODS</h3> In an 8-session, participatory group model-building process, patient, caregiver, clinician community...
The potential utility of cultured neuroblastoma cells as donor tissue for neutral implants into the mammalian brain has been examined. Cells from a human cell line, IMR-32, were labeled with [3H]thymidine and chemically rendered amitotic. These differentiated IMR-32 grafted hippocampi five adult African Green monkeys, graft survival was evaluated up to 270 days after transplantation. Autoradiographically identified in four animals. Processes could be followed distances 150 micrometers host...
Mammalian prion structures and replication mechanisms are poorly understood. Most synthetic recombinant protein (rPrP) amyloids prepared without cofactors non-infectious or much less infectious than bona fide tissue-derived PrPSc. This effect has been associated with differences in folding of the aggregates, manifested part by reduced solvent exclusion protease-resistance rPrP amyloids, especially within residues ~90–160. Substitution 4 lysines 101–110 (central lysine cluster) alanines (K4A)...