A5085074453- Amyloidosis: Diagnosis, Treatment, Outcomes
- Alzheimer's disease research and treatments
- Enzyme Structure and Function
- Cellular transport and secretion
- Protein Structure and Dynamics
- Seismic Waves and Analysis
- Earthquake Detection and Analysis
- Parkinson's Disease Mechanisms and Treatments
- Methane Hydrates and Related Phenomena
- Dermatological and Skeletal Disorders
- Connective tissue disorders research
- Cardiomyopathy and Myosin Studies
- Peptidase Inhibition and Analysis
- RNA Research and Splicing
- Prion Diseases and Protein Misfolding
- RNA modifications and cancer
- Glycosylation and Glycoproteins Research
- Biochemical and Structural Characterization
- Virus-based gene therapy research
- Antifungal resistance and susceptibility
- Lysosomal Storage Disorders Research
- RNA regulation and disease
- Endoplasmic Reticulum Stress and Disease
- ATP Synthase and ATPases Research
- Parathyroid Disorders and Treatments
The University of Texas Southwestern Medical Center
2021-2024
Southwestern Medical Center
2021-2024
Center for Cancer Research
2024
National Cancer Institute
2024
University of California, Los Angeles
2022-2023
Howard Hughes Medical Institute
2019-2022
UCLA Health
2019
University of Otago
2013
Abstract ATTR amyloidosis is caused by the deposition of transthyretin in form amyloid fibrils virtually every organ body, including heart. This systemic leads to a phenotypic variability that has not been molecularly explained yet. In brain conditions, previous studies suggest an association between clinical phenotype and molecular structures their fibrils. Here we investigate whether there such ATTRv patients carrying mutation I84S. Using cryo-electron microscopy, determined cardiac...
Abstract Amyloid-forming proteins such α-synuclein and tau, which are implicated in Alzheimer’s Parkinson’s disease, can form different fibril structures or strains with distinct toxic properties, seeding activities pathology. Understanding the determinants contributing to formation of amyloid features could open new avenues for developing disease-specific diagnostics therapies. Here we report that O-GlcNAc modification monomers results core structure, as revealed by cryogenic electron...
In neurodegenerative diseases including Alzheimer’s and amyotrophic lateral sclerosis, proteins that bind RNA are found in aggregated forms autopsied brains. Evidence suggests aids nucleation of these pathological aggregates; however, the mechanism has not been investigated at level atomic structure. Here, we present 3.4-Å resolution structure fibrils full-length recombinant tau protein presence RNA, determined by electron cryomicroscopy (cryo-EM). The reveals familiar in-register cross-β...
Despite much effort, antibody therapies for Alzheimer’s disease (AD) have shown limited efficacy. Challenges to the rational design of effective antibodies include difficulty achieving specific affinity critical targets, poor expression, and aggregation caused by buried charges unstructured loops. To overcome these challenges, we grafted previously determined sequences fibril-capping amyloid inhibitors onto a camel heavy chain scaffold. These were designed cap fibrils tau, known form...
Amyloidogenic transthyretin (ATTR) amyloidosis is a relentlessly progressive disease caused by the misfolding and systemic accumulation of amyloidogenic into amyloid fibrils. These fibrils cause diverse clinical phenotypes, mainly cardiomyopathy and/or polyneuropathy. Little known about aggregation during development whether this has implications for diagnosis treatment. Using cryogenic electron microscopy structures mature ATTR fibrils, we developed peptide probe fibril detection. With...
ATTR amyloidosis results from the conversion of transthyretin into amyloid fibrils that deposit in tissues causing organ failure and death. This is facilitated by mutations ATTRv amyloidosis, or aging ATTRwt amyloidosis. exhibits extreme phenotypic variability, whereas presentation consistent predictable. Previously, we found unique structural variabilities cardiac polyneuropathic ATTRv-I84S patients. In contrast, five genotypically different patients with cardiomyopathy mixed phenotypes are...
Abstract ATTR amyloidosis is a phenotypically heterogeneous disease characterized by the pathological deposition of transthyretin in form amyloid fibrils into various organs. may stem from mutations variant (ATTRv) amyloidosis, or aging wild-type (ATTRwt) amyloidosis. ATTRwt generally manifests as cardiomyopathy phenotype, whereas ATTRv present polyneuropathy, cardiomyopathy, mixed, combination with many other symptoms deriving secondary organ involvement. Over 130 different mutational...
Abstract ATTR amyloidosis results from the conversion of transthyretin into amyloid fibrils that deposit in tissues causing organ failure and death. This is facilitated by mutations ATTRv amyloidosis, or aging ATTRwt amyloidosis. exhibits extreme phenotypic variability, whereas presentation consistent predictable. Previously, we found an unprecedented structural variability cardiac polyneuropathic ATTRv-I84S patients. In contrast, five genotypically-different patients with cardiomyopathy...
ATTR amyloidosis is a relentlessly progressive disease caused by the misfolding and systemic accumulation of amyloidogenic transthyretin into amyloid fibrils. These fibrils cause diverse clinical phenotypes, mainly cardiomyopathy and/or polyneuropathy. Little known about aggregation during development whether this has implications for diagnosis treatment. Using cryogenic electron microscopy structures mature fibrils, we developed peptide probe fibril detection. With probe, have identified...
ATTR amyloidosis is a degenerative disorder characterized by the systemic deposition of protein transthyretin. These amyloid aggregates transthyretin (ATTR) can deposit in different parts body causing diverse clinical manifestations. Our laboratory aims to investigate potential relationship between genotypes, organ deposition, phenotypes, and structure fibrils. Using cryo-electron microscopy, we have recently described how neuropathic related mutations ATTRv-I84S ATTRv-V122∆ drive structural...
ABSTRACT The process of amyloid fibril formation remains one the primary targets for developing diagnostics and treatments several neurodegenerative diseases (NDDs). Amyloid-forming proteins such α-Synuclein Tau, which are implicated in pathogenesis Alzheimer’s Parkinson’s disease, can form different types structure, or strains, that exhibit distinct structures, toxic properties, seeding activities, pathology spreading patterns brain. Therefore, understanding molecular structural...
ATTR amyloidosis is a systemic disease characterized by the deposition of amyloid fibrils made transthyretin, protein integral to transporting retinol and thyroid hormones. Transthyretin primarily produced liver circulates in blood as tetramer. The retinal epithelium also secretes which secreted vitreous humor eye. Because mutations or aging, transthyretin can dissociate into amyloidogenic monomers triggering fibril formation. myocardium peripheral nerves causes cardiomyopathies...
ABSTRACT Lenacapavir (LEN) is the first in class viral capsid protein (CA) targeting antiretroviral for treating multi-drug-resistant HIV-1 infection. Clinical trials and cell culture experiments have identified resistance associated mutations (RAMs) vicinity of hydrophobic CA pocket targeted by LEN. The M66I substitution conferred far highest level to inhibitor compared other RAMs. Here we investigated structural mechanistic bases how change affects LEN binding replication. high-resolution...
Abstract The deposition of amyloidogenic transthyretin (ATTR) in ATTR amyloidosis leads to an unexplained variety clinical phenotypes, including cardiomyopathy. In brain amyloid conditions, there is apparent association between the phenotype and fibril structure. Here, we question this phenotype-structure cardiac amyloidoses by determining cryo-electron microscopy structures fibrils extracted from hearts seven patients. We found that, contrast fibrils, display a structural polymorphism that...
Candida albicans is a major cause of opportunistic and life-threatening systemic fungal infections, especially in the immunocompromised. The plasma membrane proton-pumping ATPase (Pma1p) an essential enzyme that generates electrochemical gradient required for cell growth. We expressed C. Pma1p (CaPma1p) Saccharomyces cerevisiae to facilitate screening inhibitors. Replacement S. PMA1 with gave clones expressing CaPma1p grew slowly at low pH. was significantly lower levels had specific...
Abstract In neurodegenerative diseases including Alzheimer’s and ALS, proteins that bind RNA are found in aggregated forms autopsied brains. Evidence suggests aids nucleation of these pathological aggregates; however, the mechanism has not been investigated at level atomic structure. Here we present 3.4 Å resolution structure fibrils full-length recombinant tau protein presence RNA, determined by electron cryo-microscopy (cryoEM). The reveals familiar in-register cross-β amyloid scaffold,...
Assembly of the microtubule-associated protein into tauopathy fibril conformations dictates pathology a diversity diseases. Recent cryogenic Electron Microscopy (cryo-EM) structures have uncovered distinct in different tauopathies but it remains unknown how these fold from single sequence. It has been proposed that post-translational modifications may drive tau assembly no direct mechanism for emerged. Leveraging established aggregation-regulating fragments are normally inert, we tested...
ATTR amyloidosis is caused by the conversion of transthyretin to amyloid fibrils that deposit in virtually every organ body, including heart. This systemic deposition leads a phenotypic variability has not been molecularly explained yet. In brain conditions, previous studies suggest an association between clinical phenotype and molecular structures their fibrils. our laboratory we investigate whether associated with structure use this information develop diagnostic tools. Using cryo-electron...