Molecular Bases of Proteinopathies
2020-2021 virtual meeting of talks, activities, 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) from 10:00 AM to ~11:00 AM (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 in a YouTube channel.
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
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
December 12, 2020
January 16, 2021
"Molecular structures of glucagon and tau fibrils from NMR "
January 23, 2021
January 30, 2021
February 06, 2021
February 13, 2021
February 20, 2021
March 06, 2021
March 13, 2021
"p53 amyloid formation associated with cancer"
April 17, 2021
"Seeing the molecular details of amyloid formation"
April 24, 2021
“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.