Understanding Protein Aggregation in Disease

Can physics explain how brain proteins change during normal and accelerated aging? In this BioEssays Journal review, we propose replacing century-old clinicopathological descriptors with the language of physics. In a biophysical framework, proteins don't actively replicate like prions—they passively precipitate along a thermodynamically favorable concentration gradient. The key driver of protein aggregation is supersaturation (very high concentration), which causes proteins to precipitate into their pathological state via nucleation. There is no need to describe pathological proteins as 'templating' or encoding themselves onto others. Under electron microscopy, they are not identical copies, 'strains', but infinitely diverse fibrils: polymorphs. Proteins can only function in their monomeric state. Once aggregated into amyloids—very stable cross-β structures—proteins lose their functions. When does neurodegeneration occur? When the transition of monomeric proteins into their pathological state depletes them faster than they can be replaced. In normal aging, the supply of monomeric proteins matches demand. In accelerated aging (e.g., Parkinson's or Alzheimer's), it doesn't. Proteins do not cause diseases. There is nothing toxic about the amino acid sequence of a protein or the shape of its pathological fibrils. The therapeutic implication: Moving efforts from clearing pathological proteins to restoring monomeric proteins. Treat the depletion, not the deposition. The biophysical model for reinterpreting brain proteins could redefine the approach to Alzheimer’s, Parkinson’s, and other neurodegenerative diseases—and help retire the “toxic protein” and "toxic amyloid" narratives from the neurological literature. Full text: https://lnkd.in/gtdHNGsj Video: https://lnkd.in/gyJTKtR8 With gratitude to Kariem Ezzat, who first introduced me to the biophysics of proteins when I knew nothing about it, and to my distinguished coauthors, from whom I learned a great deal during the writing of this manuscript. #Neurodegeneration #ProteinHomeostasis #Biophysics #Aging #Parkinsons #Alzheimers #Amyloid

Tackling Insoluble Proteins: A Unified Strategy for Age-Related Illnesses The study examines how the amyloid-beta (Aβ) protein, associated with Alzheimer's disease, affects protein solubility in a C. elegans model. Researchers discovered that Aβ expression causes widespread proteins to become insoluble and aggregate. Significantly, the insoluble proteins caused by Aβ highly overlapped with the proteins that generally become insoluble during aging in C. elegans. This suggests a "core" set of proteins vulnerable to becoming insoluble under stressful conditions like Aβ expression or aging. This "core insoluble proteome" was enriched with proteins linked to Alzheimer's, Parkinson's, and Huntington's disease. Remarkably, it was also enriched with biological processes associated with various chronic age-related diseases beyond neurodegeneration, such as metabolic, cardiovascular, and cancer. By genetically reducing the levels of specific insoluble proteins or using Urolithin A to boost mitochondrial quality control, researchers could modulate the toxic effects of Aβ in the C. elegans model. The findings suggest that widespread protein insolubility may contribute to the development of neurodegenerative diseases and potentially other age-related diseases. Targeting this "core insoluble proteome" or boosting mitochondrial quality control could be potential therapeutic strategies against these diseases. The study provides insights into how protein insolubility driven by aging and disease proteins like Aβ may underlie various age-related conditions, highlighting protein solubility as an important area for developing regenerative medicine approaches. This study brings to mind a subject starting to generate more and more interest in regenerative medicine, namely Heat Shock Proteins. The authors found that cytoplasmic and organelle-specific HSPs from across major organelles were enriched in the insoluble proteome driven by Aβ expression. Proteins involved in maintaining proteostasis, including chaperones like the TriC chaperonin complex, also became insoluble due to Aβ. These observations suggest that Aβ expression overwhelms the protein quality control systems involving HSPs and other chaperones, leading to widespread protein misfolding and aggregation. The study highlights the role of Heat Shock Proteins (HSPs) in protein solubility and age-related diseases. As part of the initial defense against protein misfolding, HSPs attempt to refold or solubilize the proteins accumulating in the insoluble proteome. However, they eventually become insoluble when overwhelmed by Aβ. The insolubility of key HSPs could further contribute to the collapse of proteostasis networks, accelerating the accumulation of misfolded, aggregated proteins. Boosting HSP activity could restore proteostasis and alleviate protein insolubility driven by Aβ or aging. I reviewed the longer article but posted the shorter one. JP https://lnkd.in/eURaiA2X

This excellent paper by Wu et. al. describes studies that document decreasing hydrophobicity or shielding hydrophobic areas of CH2 attentuates low pH-induced IgG4 aggregation. Quoting from the abstract: "Protein aggregation is a major challenge in the development of therapeutic monoclonal antibodies (mAbs). Several stressors can cause protein aggregation, including temperature shifts, mechanical forces, freezing-thawing cycles, oxidants, reductants, and extreme pH. When antibodies are exposed to low pH conditions, aggregation increases dramatically. However, low pH treatment is widely used in protein A affinity chromatography and low pH viral inactivation procedures. In the development of an IgG4 subclass antibody, mAb1-IgG4 showed a strong tendency to aggregate when temporarily exposed to low pH conditions. Our findings showed that the aggregation of mAb1-IgG4 under low pH conditions is determined by the stability of the Fc. The CH2 domain is the least stable domain in mAb1-IgG4. The L309E, Q311D, and Q311E mutations in the CH2 domain significantly reduced the aggregation propensity, which could be attributed to a reduction in the hydrophobicity of the CH2 domain. Protein stabilizers, such as sucrose and mannose, could also attenuate low pH-induced mAb1-IgG4 aggregation by shielding hydrophobic areas and increasing protein stability. Our findings provide valuable strategies for managing the aggregation of protein therapeutics with a human IgG4 backbone."

Researchers Jiyoen Kim, Bakhos Tadros, Huda Yahya Zoghbi, et al. discovered that the enzyme TYK2 transforms the normal protein tau into one that accumulates in the brain and contributes to the development of #AlzheimersDisease in animal models. This study suggests that partially restraining TYK2 could be a strategy to reduce tau levels and toxicity. Learn More in Nature Neuroscience https://lnkd.in/e9fu6PCT TYK2 regulates tau levels, phosphorylation and aggregation in a tauopathy mouse model - Jiyoen Kim, Bakhos Tadros, Yan Hong Liang, YoungDoo Kim, Cristian Lasagna Reeves, Jun Young Sonn, Dah-eun Chloe Chung, Ph.D., Bradley Hyman, David M. Holtzman & Huda Yahya Zoghbi Baylor College of Medicine Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital Stark Neurosciences Research Institute Indiana University School of Medicine Harvard Medical School - Massachusetts General Hospital Hope Center for Neurological Disorders, Knight Alzheimers’ Disease Research Center, Washington University in St. Louis Howard Hughes Medical Institute (HHMI)

🚨 Breaking Ground in Neurodegenerative Research: A New Era for Tauopathy Insights🚨  Exciting advancements in the understanding of tauopathies in diseases like Alzheimer’s, Pick’s disease, corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP). A recent study published in Molecular Neurodegeneration by researchers at the Mayo Clinic and University of California, Davis introduces Probe-dependent Proximity Profiling (ProPPr), a cutting-edge technique that deciphers the protein landscapes of tau aggregates directly from human brain tissue.  LC-MS analysis was conducted on an #Evosep One (Evosep Biosystems) coupled to a Bruker timsTOF Pro 2 🔍 What’s New?   Using ProPPr, researchers mapped the proteomes of phospho-tau aggregates across four major tauopathies. This revealed:   - Shared and disease-specific proteins linked to tau pathology.   - Key players like VPS35 and LAMP2 associated with specific tau lesions.   - Novel disease-specific proteins such as GSK3α and ferritin light chain (FTL), which may inform therapeutic targets.  💡 Why It Matters:   This is the first comprehensive proteomic characterization of tau aggregates across multiple #tauopathies. The findings enhance our understanding of disease heterogeneity and pave the way for:   - Early diagnostic #biomarkers tailored to specific conditions.   - Targeted therapies addressing unique molecular mechanisms in each tauopathy.  🎯 The Big Picture:   ProPPr represents a major leap forward in neurodegenerative research by enabling unbiased protein discovery directly from #FFPE preserved human brain tissue. This innovation could transform how we diagnose and treat these devastating diseases.  The full manuscript can be read here: https://lnkd.in/ewg5vYxz Dmytro Morderer, Melissa Chloe Wren, Ph.D., Feilin Liu, Naomi Kouri, Anastasiia Maistrenko, Bilal Khalil, Ph.D., Nora Pobitzer, Michelle Salemi, Brett Phinney, Guojun Bu, Na Zhao, Dennis Dickson, Melissa E. Murray, Wilfried Rossoll #Neuroscience #Alzheimers #Neurodegeneration #Innovation #Proteomics

Tunneling nanotubes between microglia and neurons with protein aggregates The accumulation of pathological proteins is a hallmark of several neurodegenerative disorders, including Alzheimer’s disease, frontotemporal dementia and Parkinson’s disease. Proteins such as alpha-synuclein and tau can abnormally aggregate inside neurons, disrupting essential cellular function. The researchers employed cultures of neurons and microglia, derived from either mouse models or human stem cells, and used cutting-edge imaging technology to demonstrate that microglia establish contact with neurons through tunnelling nanotubes (TNTs) to alleviate them from toxic protein accumulations. In co-cultures of neurons and microglia, the team further observed that when toxic proteins accumulate within neurons, the number of TNTs connecting the two cell types increased and that these nanotubes contained alpha-synuclein and tau particles. The pathological proteins were transferred from neurons to microglia, not vice versa, where they were degraded over time. The results not only showed that microglia can effectively alleviate neurons from toxic protein burdens but that they also transfer mitochondria toward affected neurons via the same TNTs. Mitochondria are important component of cells and when they don’t function properly, it can lead to energy deficits and oxidative stress. Both alpha-synuclein and tau can impair mitochondrial activity, contributing to the dysfunction and death of neurons in neurodegenerative diseases. Remarkably, when microglia transferred healthy mitochondria to affected neurons, the scientists noticed that it restored energy production and reduced oxidative damage, effectively preserving neuronal functioning and survival. #ScienceMission #sciencenewshighlights https://lnkd.in/g8r8U8Gb

FAMU-FSU College of Engineering research shows how insulin, zinc and pH can block harmful protein clumps linked to Type 2 diabetes. Florida State University, Technical University of Munich, University of Michigan and University of Bordeaux. August 22, 2024. Key: Researchers are interested in developing drugs to break up or stop amyloid deposits from forming, which interfere in hormone production for individuals with Type 2 diabetes. Excerpt: An estimated 462 million people around the world suffer from Type 2 diabetes. New research led by Ayyalusamy Ramamoorthy, a professor at FAMU-FSU College of Engineering and the Florida State University- National High Magnetic Field Laboratory, shows how zinc, pH levels and insulin work together to inhibit buildup of protein clumps that contribute to Type 2 diabetes. The work, points toward promising paths for innovative treatments, was published in Communications Biology. Note: Research focuses on the intricate relationship between insulin and the hormone amylin, or human islet amyloid polypeptide (hiAPP). Amylin is a naturally occurring peptide hormone involved in regulating glycemia and energy balance. Human amylin can form amyloid fibers, which can destroy insulin-producing cells in the pancreas. “At the core of our research we want to understand the complex effects of insulin on amylin’s aggregation and its resultant toxicity,” said Ramamoorthy, who directed the study. “These factors are critical to understanding Type 2 diabetes pathophysiology.” “Amylin is produced in the pancreas alongside insulin and has a tendency to clump into aggregates called amyloid,” said Sam McCalpin, a post-doctoral researcher in the Ramamoorthy lab at the National High Magnetic Field Laboratory. “They’re like plaques that form in the brain with Alzheimer’s or Parkinson’s disease.” Researchers are interested in developing drugs to break up or stop the plaques from forming. For individuals with Type 2 diabetes, amylin tends to cluster into harmful amyloid plaques, devastating the islet cells responsible for hormone production. However, insulin emerges as a potential hero, showing capabilities to hinder amylin’s aggregation. This study unravels the nuances of their interaction, alongside the roles of zinc and pH levels, bringing scientists closer to decoding the cellular intricacies of diabetes. “There is evidence insulin can help, but it is not potent enough to directly affect Type 2 diabetes,” McCalpin said. “We want to use insulin as a model to engineer more effective treatments in the future.” New research will help drug development aimed at neutralizing amylin’s toxicity, Ramamoorthy said. This could potentially revolutionize treatment approaches, offering hope to those battling this pervasive illness. Nature: Communications Biology 27 June 2024 Zinc and pH modulate the ability of insulin to inhibit aggregation of islet amyloid polypeptide Direct link to publication available in enclosed announcement.

In this article, I highlight an intriguing discovery about how the brain protects itself from harmful protein aggregation, which provides promising new insights into the treatment of neurodegenerative diseases. Researchers from Dr. Joanna Wysocka's group at Stanford University in the United States studied FOXP2, a glutamine-rich transcription factor that was essential for the evolution of human language. They found that FOXP2 is able to avoid the formation of toxic polyglutamine (polyQ) aggregates thanks to two natural mechanisms: DNA binding during interphase and phosphorylation during mitosis. These mechanisms are able to maintain the protein's solubility and prevent aberrant assembly, even in the presence of long polyQ stretches - features often associated with diseases such as Huntington's disease. Remarkably, mimicking these features in disease-causing proteins can reduce their aggregation, suggesting that nature's own protective strategies can be used for therapeutic purposes. This issue also describes how evolutionary biology, epigenetics, and protein dynamics converge to inspire new therapeutics for polyQ expansion disorders. #Neurodegeneration #FOXP2 #ProteinAggregation #PolyQDisorders #HuntingtonsDisease #Phosphorylation #DNAInteraction #MolecularNeuroscience #ProteinSolubility #ScienceNewsletter #CSTEAMBiotech

UC Irvine Department of Chemistry Professor Elizabeth Bess has shown that bacteria in the gut contribute to the formation of protein chunks that play a key role in the onset of Parkinson's. Waste produced by E. coli causes protein chunks – called alpha-synucleinaggregates – to form. These protein chunks travel up the vagus nerve to the brain. They also found that a component of coffee can prevent the protein aggregates from forming in intestinal cells. And other studies have shown that drinking coffee decreases the risk of developing Parkinson’s disease. More generally, a better understanding of the cause is laying the groundwork for new treatments that target the proteins before they ever make it to the brain.

Oncogenic p53 triggers amyloid aggregation of p63 and p73 liquid droplets “The transition of p53 from a liquid to a solid state, observed in both mutant and wild-type forms, supports the hypothesis that protein phase behavior is intrinsically linked to cellular dysfunction in cancer. The novel finding that p53 can induce the amyloid aggregation of its paralogs, p63, and p73, from the droplet state advances our understanding of the molecular underpinnings of oncogenesis.” https://lnkd.in/g85KVt4f