Molecular Bases of Proteinopathies
2020-2021 virtual meeting of talks and discussion on "protein multimerization: the bad and the good"
The ZOOMinar series on “Molecular Basis of Proteinopathies” will cover recent breakthroughs in this exciting multidisciplinary area of research from experts in the field. When conferences have been canceled around the world, these virtual presentations and discussions will provide unique opportunities for everyone to learn about recent findings, new topics, and cutting-edge techniques. The live presentations are on Tuesdays (August 2020) and Saturdays (from September 2020 to August 2021) from 10:00 AM to ~11:00 AM (EDT); and Mondays (from October 2021) from 12:00 noon EST/EDT. This virtual seminar includes a ~35 minutes presentation and ~15 minutes for questions and answers. We expect that there will be about 450 to 500 researchers participating from all over the world. The virtual presentations will be recorded and made available on a YouTube channel.
October 04, 2021 Dr. Dennis J. Selkoe
August 21, 2021
Professor, Miami University, Ohio
August 4, 2020
A Hypothesis for How Innate Immune Dysregulation May Cause Alzheimer’s Dementia;
and How We May Be Able to Prevent It
We are investigating the early-stage etiology of sporadic Alzheimer's Disease (AD), for which 420+ clinical trials by Pharma have failed over the past 15 years to produce an effective drug. What causes the accumulation of Aβ peptide-rich fibrils and plaques in an aging brain? What are Aβ's physiological functions? We focus on Aβ's interactions with the human cathelicidin peptide, LL-37, an antibacterial and antiviral innate immune system effector and modulator that is ubiquitous in tissues and expressed by myriad cell types, yet unique in the human proteome. Recently, evidence has built that chronic Herpesvirus or P. gingivalis infections of human brain tissue may precipitate many cases of sporadic dementia labeled as Alzheimer’s Disease. We present experimental evidence and discuss our developing hypothesis that the antiviral and antibacterial peptide LL-37, which can be chronically under-expressed in humans based on dietary and lifestyle factors or degraded by P. gingivalis virulence factors, is a natural binding partner of Aβ that inhibits formation of AD fibrils and plaques, such that LL-37 and Aβ have a toxin/antitoxin relationship. We demonstrate binding between LL-37 and Aβ by Transmission Electron Microscopy (TEM), Surface Plasmon Resonance Imaging (SPRi), and circular dichroism (CD) spectroscopy. TEM shows that LL-37 inhibits the fibrillization of Aβ, especially the formation of long, straight fibrils characteristic of AD, while CD spectroscopy reveals that LL-37 binding prevents Aβ from adopting β-type secondary structure. Analytical Ultracentrifugation (AUC) and Small-Angle X-ray Scattering (SAXS) prove that LL-37 and Aβ form a unique, water-soluble, 1:1 complex. In vitro cell culture studies using primary human microglia and neuronal cells indicates that these two peptides neutralize each other’s cytotoxic effects on these cells. Finally, studies in 5XFAD and wildtype transgenic mice, and Drosophila Melanogaster, support these findings. We discuss what all of this means in the context of the prevention and treatment of Alzheimer’s dementia.
August 11, 2020
“Polymorphism of Protein Aggregates in Alzheimer’s Disease and Related Dementias”
August 18, 2020
“Polyglutamine-mediated proteotoxicity in SBMA"
August 25, 2020
“Specific viral RNA drives the SARS CoV-2 nucleocapsid to phase separate "
A mechanistic understanding of the SARS-CoV-2 viral replication cycle is essential to develop new therapies for the COVID-19 global health crisis. In this study, we show that the SARS-CoV-2 nucleocapsid protein (N-protein) undergoes liquid-liquid phase separation (LLPS) with the viral genome, and propose a model of viral packaging through LLPS. N-protein condenses with specific RNA sequences in the first 1000 nts (5’-End) under physiological conditions and is enhanced at human upper airway temperatures. N-protein condensates exclude non-packaged RNA sequences. We comprehensively map sites bound by N-protein in the 5’-End and find preferences for single-stranded RNA flanked by stable structured elements. Liquid-like N-protein condensates form in mammalian cells in a concentration-dependent manner and can be altered by small molecules. Condensation of N-protein is sequence and structure specific, sensitive to human body temperature, and manipulatable with small molecules thus presenting screenable processes for identifying antiviral compounds effective against SARS-CoV-2.
September 12, 2020
“Entry to peptide Wonderland through the rabbit-hole”
September 19, 2020
“IAPP cross interactions: from discovery to exploitation"
September 26, 2020
“New insights into tau prion propagation”
October 3, 2020
“Pathogenic vs Reversible Functional Amyloid"
October 10, 2020
"The Role of Intrinsic Disorder and Dynamics in Biological Phase Transitions "
October 17, 2020
“Distinct species of amyloid oligomers and their biological activities”
October 24, 2020
“The complex landscape of α-synuclein”
October 31, 2020
“Molecular underpinnings of the life and death of Tau"
November 7, 2020
“Computational studies on the effects of in vivo conditions on amyloid-β aggregation”
November 14, 2020
“How chaperones regulate protein phase transition and its role in neurodegenerative disease”
November 21, 2020
"Tracking the dynamic conformation ensemble of tau along its aggregation pathway"
December 5, 2020
"Virulent and Antibacterial Fibrils in Infectious and Aggregation Diseases"
December 12, 2020
"Interference with protein aggregation at the membrane: structural biology and therapy"
College of Medicine Molecular Medicine
University of South Florida
December 19, 2020
"From polyfunctionality to multipathogenicity with intrinsic disorder"
Elisar Barbar & Heather Forsythe
Professor (Dr. Elisar Barbar)
Graduate Student (Heather Forsythe)
Faculty Director of the Oregon State University Biomolecular NMR Facility, and Department Head
January 09, 2020
"Multivalency and protein disorder in virus protein interactions: Common themes among Rabies virus and SARS-CoV2"
January 23, 2021
"Investigating the role of N-terminal acetylation on alpha-synuclein structure and function"
January 30, 2021
"Repeat associated non-AUG (RAN) translation in neurodegenerative disease: molecular insights and therapeutic opportunities"
February 06, 2021
"Metabolite Self-Assembly: Extension of the amyloid hypothesis"
"Aβ oligomer disassembly into monomers is beneficial for cognition and memory in transgenic and non-transgenic Alzheimer animal models"
"Heterogeneity of Aβ Aggregates"
February 27, 2021
"Replica-exchange simulations on the conformational dynamics of spike protein on the surface of SARS-CoV-2"
"The intrinsically disordered membrane anchor of Ras proteins sorts membrane lipids"
"p53 amyloid formation associated with cancer"
"The roles of monomer and membrane in Aβ-protein genesis and aggregation"
on March 27th and April 3rd
Enjoy the break!
April 10, 2021
Tata Institute of Fundamental Research,
Mumbai 400005, INDIA
Email: email@example.com, URL: biophotonics.co.in
“Probing toxic protein oligomers: From test tubes to patient-derived neurons”
"Seeing the molecular details of amyloid formation"
April 17, 2021
"A short motif in the N-terminal region of alpha-synuclein is critical for aggregation"
“Role of α-synuclein phosphorylation at serine 129 in the pathogenesis of synucleinopathies: an active debate"
Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are human neurodegenerative diseases characterized neuropathologically by the presence of neuronal α-synuclein inclusions, named as Lewy bodies and Lewy neurites. Increasing number of studies highlighted the aberrant accumulation of phosphorylated α-synuclein at the residue Serine129 (pS129) in the brain of PD and DLB patients, suggesting that phosphorylation may play a vital role in the regulation of α-synuclein aggregation and subsequent neuronal degeneration. However, a comprehensive understating of the exact role of α-synuclein phosphorylation at S129 is still lacking. Here, we study the time-point at which pS129 modification occurs in the process of α-synuclein aggregation and its role in initiation, progression and cellular toxicity of the disease. Therefore, with the collaboration of many international teams we have addressed this issue by designing and executing important in vitro, ex vivo, and in vivo experiments using various models, in addition to post-mortem human brain studies. Contrary to the putative view of pS129-α-synuclein being particularly disease-relevant form of α-synuclein, we suggest that pS129 diminished aggregation-propensity, attenuated cytotoxicity, and occurs subsequent to initial α-synuclein aggregation. Our novel findings have important implications for the design of future neuropathological studies and the development of therapeutic approaches targeting of distinct α-synuclein species.
April 24, 2021
"Protein (mis)folding at high sensitivity and resolution as seen by solid-state NMR"
May 01, 2021
"Cellular mechanisms of IAPP-induced islet beta cell dysfunction in diabetes"
"In-cell NMR: a powerful approach for studying protein folding and maturation"
Weill Cornell Medical College
"Structure-function studies of the Parkinson’s protein alpha-synuclein"
"The structural biology of protein misfolding in Huntington’s disease"
Boston University School of Medicine
"Stabilizing Antibody Light Chains to Prevent Amyloidosis"
May 22, 2021
May 22, 2021
"Small Molecule Modifiers of Toxic Protein Aggregation in Neurodegenerative and Aging Diseases: Discovery and Mechanisms"
June 05, 2021
"Membrane Protein Super-Trafficking as a Disease Mechanism: The KCNQ1 Potassium Channel and Atrial Fibrillation"
Assistant Professor, University of Michigan
"Designing fibril-specific nanobodies to inhibit alpha-synuclein pathology development"
Assistant Professor, University of Utrecht
"Understanding amyloid formation in vivo using C. elegans models of polyglutamine aggregation"
July 3, 2021: No Zoominar
July 10, 2021
July 17, 2021
"Conformational properties of immunoglobulin light chain fibrils probed by MAS solid-state NMR"
July 24, 2021
"Deregulated immune-inflammatory and neurogenic events contribute to the pathogenesis of Alzheimer's disease"
July 31, 2021
Assistant Professor, UCSD
"Understanding the molecular basis of protein phase transformations with solid-state NMR and computational approaches"
August 07, 2021
Professor, University of Michigan, Ann Arbor
"Untangling the Complexity of Protein Misfolding Diseases with Ion Mobility-Mass Spectrometry"
August 07, 2021
"Structural insights into the early stages of protein amyloid formation from mass spectrometry"
August 14, 2021
"Disaggregation of Tau fibrils and possible consequences"
August 21, 2021
Professor, Miami University, Ohio
"Solid-state and EPR Spectroscopic Studies to Probe the Structure and Topology of the Active and Inactive Forms of the Pinholin Membrane Protein"
A committee will evaluate the video presentations and will finalize the list of candidates for live presentations (~20 minutes, 10 minutes Q&A).
Committee: Dr. Martin Muschol (Chair) (Univ. of South Florida), Yifat Miller Ben Gurion Univ, Israel), Yanzhuang Wang (Univ of Michigan), Anirban Bhunia (Bose Research Institute, India), Michele Sciacca (CNRS, Catania), Sandrine Ongeri (CNRS/Université Paris Saclay).
Presentation Evaluation Committee: Dr. Bikash Sahoo (Chair) (Univ. of Michigan), Dr. Michael Bekier (Univ. of Michigan), Dr. Samuel Kotler (NIH), Anoop Arunagiri (Univ of Michigan), Sunil Kumar (University of Denver), Jose L. Arenas (CNRS/Université Paris Saclay).