More Like this

1. Prion-like spreading of Alzheimer’s disease within the brain’s connectome

   https://doi.org/10.1098/rsif.2019.0356  

   Fornari, Sveva; Schäfer, Amelie; Jucker, Mathias; Goriely, Alain; Kuhl, Ellen (October 2019, Journal of The Royal Society Interface)

   null (Ed.)

   The prion hypothesis states that misfolded proteins can act as infectious agents that template the misfolding and aggregation of healthy proteins to transmit a disease. Increasing evidence suggests that pathological proteins in neurodegenerative diseases adopt prion-like mechanisms and spread across the brain along anatomically connected networks. Local kinetic models of protein misfolding and global network models of protein spreading provide valuable insight into several aspects of prion-like diseases. Yet, to date, these models have not been combined to simulate how pathological proteins multiply and spread across the human brain. Here, we create an efficient and robust tool to simulate the spreading of misfolded protein using three classes of kinetic models, the Fisher–Kolmogorov model, the Heterodimer model and the Smoluchowski model. We discretize their governing equations using a human brain network model, which we represent as a weighted Laplacian graph generated from 418 brains from the Human Connectome Project. Its nodes represent the anatomic regions of interest and its edges are weighted by the mean fibre number divided by the mean fibre length between any two regions. We demonstrate that our brain network model can predict the histopathological patterns of Alzheimer’s disease and capture the key characteristic features of finite-element brain models at a fraction of their computational cost: simulating the spatio-temporal evolution of aggregate size distributions across the human brain throughout a period of 40 years takes less than 7 s on a standard laptop computer. Our model has the potential to predict biomarker curves, aggregate size distributions, infection times, and the effects of therapeutic strategies including reduced production and increased clearance of misfolded protein. 

   more » « less
2. Intra-FCY1: a novel system to identify mutations that cause protein misfolding

   https://doi.org/10.3389/fgene.2023.1198203  

   Quan, N; Eguchi, Y; Geiler-Samerotte, K (September 2023, Frontiers in Genetics)

   Protein misfolding is a common intracellular occurrence. Most mutations to coding sequences increase the propensity of the encoded protein to misfold. These misfolded molecules can have devastating effects on cells. Despite the importance of protein misfolding in human disease and protein evolution, there are fundamental questions that remain unanswered, such as, which mutations cause the most misfolding? These questions are difficult to answer partially because we lack high-throughput methods to compare the destabilizing effects of different mutations. Commonly used systems to assess the stability of mutant proteinsin vivooften rely upon essential proteins as sensors, but misfolded proteins can disrupt the function of the essential protein enough to kill the cell. This makes it difficult to identify and compare mutations that cause protein misfolding using these systems. Here, we present a novelin vivosystem named Intra-FCY1that we use to identify mutations that cause misfolding of a model protein [yellow fluorescent protein (YFP)] inSaccharomyces cerevisiae. The Intra-FCY1system utilizes two complementary fragments of the yeast cytosine deaminase Fcy1, a toxic protein, into which YFP is inserted. When YFP folds, the Fcy1 fragments associate together to reconstitute their function, conferring toxicity in media containing 5-fluorocytosine and hindering growth. But mutations that make YFP misfold abrogate Fcy1 toxicity, thus strains possessing misfolded YFP variants rise to high frequency in growth competition experiments. This makes such strains easier to study. The Intra-FCY1system cancels localization of the protein of interest, thus can be applied to study the relative stability of mutant versions of diverse cellular proteins. Here, we confirm this method can identify novel mutations that cause misfolding, highlighting the potential for Intra-FCY1to illuminate the relationship between protein sequence and stability. 

   more » « less
3. Yeast derlin Dfm1 employs a chaperone-like function to resolve misfolded membrane protein stress

   https://doi.org/10.1371/journal.pbio.3001950  

   Kandel, Rachel; Jung, Jasmine; Syau, Della; Kuo, Tiffany; Songster, Livia; Horn, Casey; Chapman, Claire; Aguayo, Analine; Duttke, Sascha; Benner, Christopher; et al (January 2023, PLOS Biology)

   Jakob, Ursula H. (Ed.)

   Protein aggregates are a common feature of diseased and aged cells. Membrane proteins comprise a quarter of the proteome, and yet, it is not well understood how aggregation of membrane proteins is regulated and what effects these aggregates can have on cellular health. We have determined in yeast that the derlin Dfm1 has a chaperone-like activity that influences misfolded membrane protein aggregation. We establish that this function of Dfm1 does not require recruitment of the ATPase Cdc48 and it is distinct from Dfm1’s previously identified function in dislocating misfolded membrane proteins from the endoplasmic reticulum (ER) to the cytosol for degradation. Additionally, we assess the cellular impacts of misfolded membrane proteins in the absence of Dfm1 and determine that misfolded membrane proteins are toxic to cells in the absence of Dfm1 and cause disruptions to proteasomal and ubiquitin homeostasis. 

   more » « less
4. Reduced Reelin Expression in the Hippocampus after Traumatic Brain Injury

   https://doi.org/10.3390/biom10070975  

   Dal Pozzo, Valentina; Crowell, Beth; Briski, Nicholas; Crockett, David P.; D’Arcangelo, Gabriella (July 2020, Biomolecules)

   null (Ed.)

   Traumatic brain injury (TBI) is a relatively common occurrence following accidents or violence, and often results in long-term cognitive or motor disability. Despite the high health cost associated with this type of injury, presently there are no effective treatments for many neurological symptoms resulting from TBI. This is due in part to our limited understanding of the mechanisms underlying brain dysfunction after injury. In this study, we used the mouse controlled cortical impact (CCI) model to investigate the effects of TBI, and focused on Reelin, an extracellular protein that critically regulates brain development and modulates synaptic activity in the adult brain. We found that Reelin expression decreases in forebrain regions after TBI, and that the number of Reelin-expressing cells decrease specifically in the hippocampus, an area of the brain that plays an important role in learning and memory. We also conducted in vitro experiments using mouse neuronal cultures and discovered that Reelin protects hippocampal neuronal cells from glutamate-induced neurotoxicity, a well-known secondary effect of TBI. Together our findings suggest that the loss of Reelin expression may contribute to neuronal death in the hippocampus after TBI, and raise the possibility that increasing Reelin levels or signaling activity may promote functional recovery. 

   more » « less
5. Role of Surfactant Protein D in Experimental Otitis Media

   https://doi.org/10.1159/000513605  

   Abdel-Razek, Osama; Liu, Tianyi; Chen, Xinghua; Wang, Qiushi; Vanga, Gautam; Wang, Guirong (September 2021, Journal of Innate Immunity)

   Surfactant protein D (SP-D) is a C-type collectin and plays an important role in innate immunity and homeostasis in the lung. This study studied SP-D role in the nontypeable Haemophilus influenzae (NTHi)-induced otitis media (OM) mouse model. Wild-type C57BL/6 (WT) and SP-D knockout (KO) mice were used in this study. Mice were injected in the middle ear (ME) with 5 μL of NTHi bacterial solution (3.5 × 10⁵ CFU/ear) or with the same volume of sterile saline (control). Mice were sacrificed at 3 time points, days 1, 3, and 7, after treatment. We found SP-D expression in the Eustachian tube (ET) and ME mucosa of WT mice but not in SP-D KO mice. After infection, SP-D KO mice showed more intense inflammatory changes evidenced by the increased mucosal thickness and inflammatory cell infiltration in the ME and ET compared to WT mice (p < 0.05). Increased bacterial colony-forming units and cytokine (IL-6 and IL-1β) levels in the ear washing fluid of infected SP-D KO mice were compared to infected WT mice. Molecular analysis revealed higher levels of NF-κB and NLRP3 activation in infected SP-D KO compared to WT mice (p < 0.05). In vitro studies demonstrated that SP-D significantly induced NTHi bacterial aggregation and enhanced bacterial phagocytosis by macrophages (p < 0.05). Furthermore, human ME epithelial cells showed a dose-dependent increased expression of NLRP3 and SP-D proteins after LPS treatment. We conclude that SP-D plays a critical role in innate immunity and disease resolution through enhancing host defense and regulating inflammatory NF-κB and NLRP3 activation in experimental OM mice. 

   more » « less