bims-proned 2024-09-15 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2024‒09‒15
nineteen papers selected by
Verena Kohler, Umeå University

Multivalency drives interactions of alpha-synuclein fibrils with tau.
The Role of α-Synuclein in Etiology of Neurodegenerative Diseases.
[Disease-modifying Drugs for non-Alzheimer Dementias].
Study of Insulin Aggregation and Fibril Structure under Different Environmental Conditions.
Bifunctional Inhibitor Lentinan Inhibits Fibrillogenesis of Amyloid-β Protein and α-Synuclein and Alleviates Their Cytotoxicity: In Vitro and In Vivo Studies.
Two novel DnaJ chaperone proteins CG5001 and P58IPK regulate the pathogenicity of Huntington's disease related aggregates.
Engineered NLS-chimera downregulates expression of aggregation-prone endogenous FUS.
DBT is a metabolic switch for maintenance of proteostasis under proteasomal impairment.
Peptide-Based Strategies: Combating Alzheimer's Amyloid β Aggregation through Ergonomic Design and Fibril Disruption.
α-Synuclein strain propagation is independent of cellular prion protein expression in a transgenic synucleinopathy mouse model.
Gut-induced alpha-Synuclein and Tau propagation initiate Parkinson's and Alzheimer's disease co-pathology and behavior impairments.
The Bifunctional Dimer Caffeine-Indan Attenuates α-Synuclein Misfolding, Neurodegeneration and Behavioral Deficits after Chronic Stimulation of Adenosine A1 Receptors.
HIV-1 Vpu induces neurotoxicity by promoting Caspase 3-dependent cleavage of TDP-43.
Unraveling the Hydration Dynamics of the ACC1-13K24-ATP System: From Liquid-to-Droplet to-Amyloid Fibril.
Investigating the Mechanisms of Antibody Binding to Alpha-Synuclein for the Treatment of Parkinson's Disease.
Production of Distinct Fibrillar, Oligomeric, and Other Aggregation States from Network Models of Multibody Interaction.
Ezetimibe Lowers Risk of Alzheimer's and Related Dementias over Sevenfold, Reducing Aggregation in Model Systems by Inhibiting 14-3-3G::Hexokinase Interaction.
HGA Triggers SAA Aggregation and Accelerates Fibril Formation in the C20/A4 Alkaptonuria Cell Model.
Upregulation of NFE2L1 reduces ROS levels and α-synuclein aggregation caused by GBA1 knockdown.

PLoS One. 2024 ;19(9): e0309416

Multivalency drives interactions of alpha-synuclein fibrils with tau.

Jennifer Ramirez, Ibrahim G Saleh, Evan S K Yanagawa, Marie Shimogawa, Emily Brackhahn, E James Petersson, Elizabeth Rhoades.

Age-related neurodegenerative disorders like Alzheimer's disease (AD) and Parkinson's disease (PD) are characterized by deposits of protein aggregates, or amyloid, in various regions of the brain. Historically, aggregation of a single protein was observed to be correlated with these different pathologies: tau in AD and α-synuclein (αS) in PD. However, there is increasing evidence that the pathologies of these two diseases overlap, and the individual proteins may even promote each other's aggregation. Both tau and αS are intrinsically disordered proteins (IDPs), lacking stable secondary and tertiary structure under physiological conditions. In this study we used a combination of biochemical and biophysical techniques to interrogate the interaction of tau with both soluble and fibrillar αS. Fluorescence correlation spectroscopy (FCS) was used to assess the interactions of specific domains of fluorescently labeled tau with full length and C-terminally truncated αS in both monomer and fibrillar forms. We found that full-length tau as well as individual tau domains interact with monomer αS weakly, but this interaction is much more pronounced with αS aggregates. αS aggregates also mildly slow the rate of tau aggregation, although not the final degree of aggregation. Our findings suggest that co-occurrence of tau and αS in disease are more likely to occur through monomer-fiber binding interactions, rather than monomer-monomer or co-aggregation.

DOI: https://doi.org/10.1371/journal.pone.0309416
Int J Mol Sci. 2024 Aug 24. pii: 9197. [Epub ahead of print]25(17):

The Role of α-Synuclein in Etiology of Neurodegenerative Diseases.

Daria Krawczuk, Magdalena Groblewska, Jan Mroczko, Izabela Winkel, Barbara Mroczko.

  A presynaptic protein called α-synuclein plays a crucial role in synaptic function and neurotransmitter release. However, its misfolding and aggregation have been implicated in a variety of neurodegenerative diseases, particularly Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Emerging evidence suggests that α-synuclein interacts with various cellular pathways, including mitochondrial dysfunction, oxidative stress, and neuroinflammation, which contributes to neuronal cell death. Moreover, α-synuclein has been involved in the propagation of neurodegenerative processes through prion-like mechanisms, where misfolded proteins induce similar conformational changes in neighboring neurons. Understanding the multifaced roles of α-synuclein in neurodegeneration not only aids in acquiring more knowledge about the pathophysiology of these diseases but also highlights potential biomarkers and therapeutic targets for intervention in alpha-synucleinopathies. In this review, we provide a summary of the mechanisms by which α-synuclein contributes to neurodegenerative processes, focusing on its misfolding, oligomerization, and the formation of insoluble fibrils that form characteristic Lewy bodies. Furthermore, we compare the potential value of α-synuclein species in diagnosing and differentiating selected neurodegenerative diseases.

Keywords:  Parkinson’s disease; dementia with Lewy bodies; multiple system atrophy; neurodegeneration; synucleinopathies; α-synuclein

DOI:  https://doi.org/10.3390/ijms25179197
Brain Nerve. 2024 Sep;76(9): 1059-1064

[Disease-modifying Drugs for non-Alzheimer Dementias].

Takehiro Miyazaki, Shinji Higashi, Tetsuaki Arai.

Neurodegenerative diseases represent the most common cause of dementia. Protein aggregation is upstream in the pathological mechanisms and is a therapeutic target in the development of disease-modifying drugs in this patient population. Notably, α-synuclein or DNA-binding protein of 43kDa (TDP-43) is commonly involved in the pathomechanisms that contribute to non-Alzheimer neurodegenerative diseases. Several immunotherapy clinical trials on α-synuclein have progressed to phase 2, and small-molecule therapeutics are ongoing. With regard to TDP-43, immunotherapies that target protein aggregates are currently being developed, and research is underway to investigate several drugs that target the associated causative gene. Further research is warranted for deeper insight into both disease-modifying drugs; biomarker tests need to be developed to determine their efficacy. However, both proteins aggregate and accumulate in the brain in many neurodegenerative diseases and dementia; therefore, they are therapeutically significant, and future progress is expected in research and development.

DOI: https://doi.org/10.11477/mf.1416202733
Int J Mol Sci. 2024 Aug 29. pii: 9406. [Epub ahead of print]25(17):

Study of Insulin Aggregation and Fibril Structure under Different Environmental Conditions.

Mantas Ziaunys, Kamile Mikalauskaite, Andrius Sakalauskas, Vytautas Smirnovas.

  Protein amyloid aggregation is linked with widespread and fatal neurodegenerative disorders as well as several amyloidoses. Insulin, a small polypeptide hormone, is associated with injection-site amyloidosis and is a popular model protein for in vitro studies of amyloid aggregation processes as well as in the search for potential anti-amyloid compounds. Despite hundreds of studies conducted with this specific protein, the procedures used have employed a vast array of different means of achieving fibril formation. These conditions include the use of different solution components, pH values, ionic strengths, and other additives. In turn, this variety of conditions results in the generation of fibrils with different structures, morphologies and stabilities, which severely limits the possibility of cross-study comparisons as well as result interpretations. In this work, we examine the condition-structure relationship of insulin amyloid aggregation under a range of commonly used pH and ionic strength conditions as well as solution components. We demonstrate the correlation between the reaction solution properties and the resulting aggregation kinetic parameters, aggregate secondary structures, morphologies, stabilities and dye-binding modes.

Keywords:  amyloids; environmental conditions; fibril structure; insulin; protein aggregation

DOI:  https://doi.org/10.3390/ijms25179406
ACS Chem Neurosci. 2024 Sep 12.

Bifunctional Inhibitor Lentinan Inhibits Fibrillogenesis of Amyloid-β Protein and α-Synuclein and Alleviates Their Cytotoxicity: In Vitro and In Vivo Studies.

Wen Gao, Qinchen Dong, Xinni Wu, Yang Wang, Jinbi Li, Qingfu Zhang, Fuping Lu, Fufeng Liu.

  Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative diseases in the world. Misfolding of β-amyloid (Aβ) and α-synuclein (α-syn) and subsequent fibril formation are closely associated with the pathogenesis of AD and PD, respectively. Lentinan is a natural product commonly used in medicine and dietary supplements. It has potential antitumor, anti-inflammatory, and antiviral effects, but the underlying mechanism of its action on AD and PD remains unclear. In this study, lentinan inhibited the formation of Aβ and α-syn fibers in a dose-dependent manner and disrupted their mature fibers. Lentinan inhibited the conversion of Aβ and α-syn conformations to β-sheet-rich conformations. Additionally, lentinan protected Caenorhabditis elegans against damage caused by the accumulation of Aβ and α-syn aggregation and prolonged their lifespan. Notably, the beneficial effects of lentinan in AD and PD mice were also demonstrated, including ameliorating the cognitive and memory impairments in AD mice and behavioral deficits in PD mice. Finally, molecular interactions between lentinan and Aβ/α-syn pentamers were also explored using molecular docking.

Keywords:  amyloid-β; inhibitor; lentinan; neurodegenerative disease; α-synuclein

DOI:  https://doi.org/10.1021/acschemneuro.4c00164
Sci Rep. 2024 09 06. 14(1): 20867

Two novel DnaJ chaperone proteins CG5001 and P58IPK regulate the pathogenicity of Huntington's disease related aggregates.

Ankita Deo, Rishita Ghosh, Snehal Ahire, Sayali Marathe, Amitabha Majumdar, Tania Bose.

  Huntington's disease (HD) is a rare neurodegenerative disease caused due to aggregation of Huntingtin (HTT) protein. This study involves the cloning of 40 DnaJ chaperones from Drosophila, and overexpressing them in yeasts and fly models of HD. Accordingly, DnaJ chaperones were catalogued as enhancers or suppressors based on their growth phenotypes and aggregation properties. 2 of the chaperones that came up as targets were CG5001 and P58IPK. Protein aggregation and slow growth phenotype was rescued in yeasts, S2 cells, and Drosophila transgenic lines of HTT103Q with these overexpressed chaperones. Since DnaJ chaperones have protein sequence similarity across species, they can be used as possible tools to combat the effects of neurodegenerative diseases.

Keywords:  DnaJ chaperones; Huntington’s disease; Neurodegenerative disease; Protein aggregation; Yeast genetics

DOI:  https://doi.org/10.1038/s41598-024-71065-3
Nat Commun. 2024 Sep 10. 15(1): 7887

Engineered NLS-chimera downregulates expression of aggregation-prone endogenous FUS.

Miyuki Hayashi, Amandeep Girdhar, Ying-Hui Ko, Kevin M Kim, Jacquelyn A DePierro, Joseph R Buchler, Nikhita Arunprakash, Aditya Bajaj, Gino Cingolani, Lin Guo.

Importin β-superfamily nuclear import receptors (NIRs) mitigate mislocalization and aggregation of RNA-binding proteins (RBPs), like FUS and TDP-43, which are implicated in neurodegenerative diseases. NIRs potently disaggregate RBPs by recognizing their nuclear localization signal (NLS). However, disease-causing mutations in NLS compromise NIR binding and activity. Here, we define features that characterize the anti-aggregation activity of NIR and NLS. We find that high binding affinity between NIR and NLS, and optimal NLS location relative to the aggregating domain plays a role in determining NIR disaggregation activity. A designed FUS chimera (FUSIBB), carrying the importin β binding (IBB) domain, is solubilized by importin β in vitro, translocated to the nucleus in cultured cells, and downregulates the expression of endogenous FUS. In this study, we posit that guiding the mutual recognition of NLSs and NIRs will aid the development of therapeutics, illustrated by the highly soluble FUSIBB replacing the aggregation-prone endogenous FUS.

DOI: https://doi.org/10.1038/s41467-024-52151-6
Elife. 2024 Sep 10. pii: RP91002. [Epub ahead of print]12

DBT is a metabolic switch for maintenance of proteostasis under proteasomal impairment.

Ran-Der Hwang, YuNing Lu, Qing Tang, Goran Periz, Giho Park, Xiangning Li, Qiwang Xiang, Yang Liu, Tao Zhang, Jiou Wang.

  Proteotoxic stress impairs cellular homeostasis and underlies the pathogenesis of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). The proteasomal and autophagic degradation of proteins are two major pathways for protein quality control in the cell. Here, we report a genome-wide CRISPR screen uncovering a major regulator of cytotoxicity resulting from the inhibition of the proteasome. Dihydrolipoamide branched chain transacylase E2 (DBT) was found to be a robust suppressor, the loss of which protects against proteasome inhibition-associated cell death through promoting clearance of ubiquitinated proteins. Loss of DBT altered the metabolic and energetic status of the cell and resulted in activation of autophagy in an AMP-activated protein kinase (AMPK)-dependent mechanism in the presence of proteasomal inhibition. Loss of DBT protected against proteotoxicity induced by ALS-linked mutant TDP-43 in Drosophila and mammalian neurons. DBT is upregulated in the tissues of ALS patients. These results demonstrate that DBT is a master switch in the metabolic control of protein quality control with implications in neurodegenerative diseases.

Keywords:  ES cell; cell culture; fruit flies; human; neuroscience

DOI:  https://doi.org/10.7554/eLife.91002
Biochemistry. 2024 Sep 10.

Peptide-Based Strategies: Combating Alzheimer's Amyloid β Aggregation through Ergonomic Design and Fibril Disruption.

Ranit Pariary, Gourav Shome, Sujan Kalita, Sourav Kalita, Anuradha Roy, Amaravadhi Harikishore, Kuladip Jana, Dulal Senapati, Bhubaneswar Mandal, Atin Kumar Mandal, Anirban Bhunia.

Amyloidosis of amyloid-β (Aβ) triggers a cascade of events, leading to oxidative damage and neuronal death. Therefore, inhibiting Aβ amyloidosis or disrupting the matured fibrils is the primary target to combat progressive Alzheimer's disease (AD) pathogenesis. Here, we undertake optimization strategies to improve the antiamyloid efficiency of our previously reported NF11 (NAVRWSLMRPF) peptide. Among the series of peptides tested, nontoxic and serum-stable peptide 1 or P1 containing an anthranilic acid residue shows immense potential in not only inhibiting the Aβ42 amyloid formation but also disrupting the mature Aβ42 fibrils into nontoxic small molecular weight soluble species. Our studies provide high-resolution characterization of the peptide's mechanism of action. With a binding affinity within the micromolar range for both the monomer and aggregated Aβ42, this α/β hybrid peptide can efficiently modulate Aβ amyloidosis while facilitating the clearance of toxic aggregates and enforcing protection from apoptosis. Thus, our studies highlight that incorporating a β-amino acid not only imparts protection from proteolytic degradation and improved stability but also functions effectively as a β breaker, redirecting the aggregation kinetics toward off-pathway fibrillation.

DOI: https://doi.org/10.1021/acs.biochem.4c00371
PLoS Pathog. 2024 Sep;20(9): e1012517

α-Synuclein strain propagation is independent of cellular prion protein expression in a transgenic synucleinopathy mouse model.

Raphaella W L So, Genki Amano, Erica Stuart, Aeen Ebrahim Amini, Adriano Aguzzi, Graham L Collingridge, Joel C Watts.

The cellular prion protein, PrPC, has been postulated to function as a receptor for α-synuclein, potentially facilitating cell-to-cell spreading and/or toxicity of α-synuclein aggregates in neurodegenerative disorders such as Parkinson's disease. Previously, we generated the "Salt (S)" and "No Salt (NS)" strains of α-synuclein aggregates that cause distinct pathological phenotypes in M83 transgenic mice overexpressing A53T-mutant human α-synuclein. To test the hypothesis that PrPC facilitates the propagation of α-synuclein aggregates, we produced M83 mice that either express or do not express PrPC. Following intracerebral inoculation with the S or NS strain, the absence of PrPC in M83 mice did not prevent disease development and had minimal influence on α-synuclein strain-specified attributes such as the extent of cerebral α-synuclein deposition, selective targeting of specific brain regions and cell types, the morphology of induced α-synuclein deposits, and the structural fingerprints of protease-resistant α-synuclein aggregates. Likewise, there were no appreciable differences in disease manifestation between PrPC-expressing and PrPC-lacking M83 mice following intraperitoneal inoculation of the S strain. Interestingly, intraperitoneal inoculation with the NS strain resulted in two distinct disease phenotypes, indicative of α-synuclein strain evolution, but this was also independent of PrPC expression. Overall, these results suggest that PrPC plays at most a minor role in the propagation, neuroinvasion, and evolution of α-synuclein strains in mice that express A53T-mutant human α-synuclein. Thus, other putative receptors or cell-to-cell propagation mechanisms may have a larger effect on the spread of α-synuclein aggregates during disease.

DOI: https://doi.org/10.1371/journal.ppat.1012517
Neuron. 2024 Aug 30. pii: S0896-6273(24)00576-2. [Epub ahead of print]

Gut-induced alpha-Synuclein and Tau propagation initiate Parkinson's and Alzheimer's disease co-pathology and behavior impairments.

Jie Xiang, Jingrong Tang, Fei Kang, Jiajun Ye, Yueying Cui, Zhentao Zhang, Jing Wang, Shengxi Wu, Keqiang Ye.

  Tau interacts with α-Synuclein (α-Syn) and co-localizes with it in the Lewy bodies, influencing α-Syn pathology in Parkinson's disease (PD). However, whether these biochemical events regulate α-Syn pathology spreading from the gut into the brain remains incompletely understood. Here, we show that α-Syn and Tau co-pathology is spread into the brain in gut-inducible SYN103+/- and/or TAU368+/- transgenic mouse models, eliciting behavioral defects. Gut pathology was initially observed, and α-Syn or Tau pathology was subsequently propagated into the DMV or NTS and then to other brain regions. Remarkably, more extensive spreading and widespread neuronal loss were found in double transgenic mice (Both) than in single transgenic mice. Truncal vagotomy and α-Syn deficiency significantly inhibited synucleinopathy or tauopathy spreading. The α-Syn PET tracer [18F]-F0502B detected α-Syn aggregates in the gut and brain. Thus, α-Syn and Tau co-pathology can propagate from the gut to the brain, triggering behavioral disorders.

Keywords:  Parkinson’s disease; Tau N368; behavioral impairment; brain-gut axis; dopaminergic neuronal loss; mouse model; α-Syn N103; α-Syn PET tracer

DOI:  https://doi.org/10.1016/j.neuron.2024.08.003
Int J Mol Sci. 2024 Aug 29. pii: 9386. [Epub ahead of print]25(17):

The Bifunctional Dimer Caffeine-Indan Attenuates α-Synuclein Misfolding, Neurodegeneration and Behavioral Deficits after Chronic Stimulation of Adenosine A1 Receptors.

Elisabet Jakova, Omozojie P Aigbogun, Mohamed Taha Moutaoufik, Kevin J H Allen, Omer Munir, Devin Brown, Changiz Taghibiglou, Mohan Babu, Chris P Phenix, Ed S Krol, Francisco S Cayabyab.

  We previously found that chronic adenosine A1 receptor stimulation with N6-Cyclopentyladenosine increased α-synuclein misfolding and neurodegeneration in a novel α-synucleinopathy model, a hallmark of Parkinson's disease. Here, we aimed to synthesize a dimer caffeine-indan linked by a 6-carbon chain to cross the blood-brain barrier and tested its ability to bind α-synuclein, reducing misfolding, behavioral abnormalities, and neurodegeneration in our rodent model. Behavioral tests and histological stains assessed neuroprotective effects of the dimer compound. A rapid synthesis of the 18F-labeled analogue enabled Positron Emission Tomography and Computed Tomography imaging for biodistribution measurement. Molecular docking analysis showed that the dimer binds to α-synuclein N- and C-termini and the non-amyloid-β-component (NAC) domain, similar to 1-aminoindan, and this binding promotes a neuroprotective α-synuclein "loop" conformation. The dimer also binds to the orthosteric binding site for adenosine within the adenosine A1 receptor. Immunohistochemistry and confocal imaging showed the dimer abolished α-synuclein upregulation and aggregation in the substantia nigra and hippocampus, and the dimer mitigated cognitive deficits, anxiety, despair, and motor abnormalities. The 18F-labeled dimer remained stable post-injection and distributed in various organs, notably in the brain, suggesting its potential as a Positron Emission Tomography tracer for α-synuclein and adenosine A1 receptor in Parkinson's disease therapy.

Keywords:  1-aminoindan; N6-cyclopentyladenosine; PET-imaging; adenosine A1 receptor; biodistribution; caffeine; dimer; neuroprotection; protein misfolding; α-synucleinopathy

DOI:  https://doi.org/10.3390/ijms25179386
EMBO Rep. 2024 Sep 06.

HIV-1 Vpu induces neurotoxicity by promoting Caspase 3-dependent cleavage of TDP-43.

Jiaxin Yang, Yan Li, Huili Li, Haichen Zhang, Haoran Guo, Xiangyu Zheng, Xiao-Fang Yu, Wei Wei.

  Despite the efficacy of highly active antiretroviral therapy in controlling the incidence and mortality of AIDS, effective interventions for HIV-1-induced neurological damage and cognitive impairment remain elusive. In this study, we found that HIV-1 infection can induce proteolytic cleavage and aberrant aggregation of TAR DNA-binding protein 43 (TDP-43), a pathological protein associated with various severe neurological disorders. The HIV-1 accessory protein Vpu was found to be responsible for the cleavage of TDP-43, as ectopic expression of Vpu alone was sufficient to induce TDP-43 cleavage, whereas HIV-1 lacking Vpu failed to cleave TDP-43. Mechanistically, the cleavage of TDP-43 at Asp89 by HIV-1 relies on Vpu-mediated activation of Caspase 3, and pharmacological inhibition of Caspase 3 activity effectively suppressed the HIV-1-induced aggregation and neurotoxicity of TDP-43. Overall, these results suggest that TDP-43 is a conserved host target of HIV-1 Vpu and provide evidence for the involvement of TDP-43 dysregulation in the neural pathogenesis of HIV-1.

Keywords:  Caspase 3; HIV-1; Neurotoxicity; TDP-43; Vpu

DOI:  https://doi.org/10.1038/s44319-024-00238-y
Biophys J. 2024 Sep 11. pii: S0006-3495(24)00603-9. [Epub ahead of print]

Unraveling the Hydration Dynamics of the ACC1-13K24-ATP System: From Liquid-to-Droplet to-Amyloid Fibril.

Sampad Bag, Robert Dec, Simone Pezzotti, Rudhi Ranjan Sahoo, Gerhard Schwaab, Roland Winter, Martina Havenith.

In order to achieve a comprehensive understanding of protein aggregation processes, an exploration of solvation dynamics, a key yet intricate component of biological phenomena, is mandatory. In the present study, we used Fourier Transform Infrared Spectroscopy (FT-IR) and Terahertz(THz)-spectroscopy complemented by Atomic Force Microscopy and kinetic experiments utilizing Thioflavin T (ThT) fluorescence to elucidate the changes in solvation dynamics during liquid-liquid phase separation and subsequent amyloid fibril formation, the latter representing a transition from liquid to solid phase separation. These processes are pivotal in the pathology of neurodegenerative disorders such as Alzheimer's and Parkinson's disease. We focus on the ACC1-13K24-ATP protein complex, which undergoes fibril formation followed by droplet generation. Our investigation reveals the importance of hydration as a driving force in these processes, offering new insights into the molecular mechanisms at play.

DOI: https://doi.org/10.1016/j.bpj.2024.09.011
Mol Pharm. 2024 Sep 09.

Investigating the Mechanisms of Antibody Binding to Alpha-Synuclein for the Treatment of Parkinson's Disease.

Malcolm C Harrison, Pin-Kuang Lai.

  Parkinson's disease (PD) is an idiopathic neurodegenerative disorder with the second-highest prevalence rate behind Alzheimer's disease. The pathophysiological hallmarks of PD are both degeneration of dopaminergic neurons in the substantia nigra pars compacta and the inclusion of misfolded α-synuclein (α-syn) aggregates known as Lewy bodies. Despite decades of research for potential PD treatments, none have been developed, and developing new therapeutic agents is a time-consuming and expensive process. Computational methods can be used to investigate the properties of drug candidates currently undergoing clinical trials to determine their theoretical efficiency at targeting α-syn. Monoclonal antibodies (mAbs) are biological drugs with high specificity, and Prasinezumab (PRX002) is an mAb currently in Phase II, which targets the C-terminus (AA 118-126) of α-syn. We utilized BioLuminate and PyMol for the structure prediction and preparation of the fragment antigen-binding (Fab) region of PRX002 and 34 different conformations of α-syn. Protein-protein docking simulations were performed using PIPER, and 3 of the docking poses were selected based on the best fit. Molecular dynamics simulations were conducted on the docked protein structures in triplicate for 1000 ns, and hydrogen bonds and electrostatic and hydrophobic interactions were analyzed using MDAnalysis to determine which residues were interacting and how often. Hydrogen bonds were shown to form frequently between the HCDR2 region of PRX002 and α-syn. Free energy was calculated to determine the binding affinity. The predicted binding affinity shows a strong antibody-antigen attraction between PRX002 and α-syn. RMSD was calculated to determine the conformational change of these regions throughout the simulation. The mAb's developability was determined using computational screening methods. Our results demonstrate the efficiency and developability of this therapeutic agent.

Keywords:  Parkinson’s disease; developability; hydrogen bonds; monoclonal antibodies; protein−protein docking; root mean squared deviation

DOI:  https://doi.org/10.1021/acs.molpharmaceut.4c00879
J Chem Theory Comput. 2024 Sep 11.

Production of Distinct Fibrillar, Oligomeric, and Other Aggregation States from Network Models of Multibody Interaction.

Elizabeth M Diessner, Loring J Thomas, Carter T Butts.

Protein aggregation can produce a wide range of states, ranging from fibrillar structures and oligomers to unstructured and semistructured gel phases. Recent work has shown that many of these states can be recapitulated by relatively simple, topological models specified in terms of multibody interaction energies, providing a direct connection between aggregate intermolecular forces and aggregation products. Here, we examine a low-dimensional network Hamiltonian model (NHM) based on four basic multibody interactions found in any aggregate system. We characterize the phase behavior of this NHM family, showing that fibrils arise from a balance between elongation-inducing and contact-inhibiting forces. Complex oligomers (including annular oligomers resembling those thought to be toxic species in Alzheimer's disease) also form distinct phases in this regime, controlled in part by closure-inducing forces. We show that phase structure is largely independent of system size, and provide evidence of a rich structure of minor oligomeric phases that can arise from appropriate conditions. We characterize the phase behavior of this NHM family, demonstrating the range of ordered and disordered aggregation states possible with this set of interactions. As we show, fibrils arise from a balance between elongation-inducing and contact-inhibiting forces, existing in a regime bounded by gel-like and disaggregated phases; complex oligomers (including annular oligomers resembling those thought to be toxic species in Alzheimer's disease) also form distinct phases in this regime, controlled in part by closure-inducing forces. We show that phase structure is largely independent of system size, allowing generalization to macroscopic systems, and provide evidence of a rich structure of minor oligomeric phases that can arise from appropriate conditions.

DOI: https://doi.org/10.1021/acs.jctc.4c00916
Aging Biol. 2024 ;pii: 20240028. [Epub ahead of print]2

Ezetimibe Lowers Risk of Alzheimer's and Related Dementias over Sevenfold, Reducing Aggregation in Model Systems by Inhibiting 14-3-3G::Hexokinase Interaction.

Akshatha Ganne, Nirjal Mainali, Meenakshisundaram Balasubramaniam, Ramani Atluri, Sonu Pahal, Joseph Asante, Corey Nagel, Srikanth Vallurupalli, Robert J Shmookler Reis, Srinivas Ayyadevara.

  Numerous factors predispose to progression of cognitive impairment to Alzheimer's disease and related dementias (ADRD), most notably age, APOE(ε4) alleles, traumatic brain injury, heart disease, hypertension, obesity/diabetes, and Down's syndrome. Protein aggregation is diagnostic for neurodegenerative diseases, and may be causal through promotion of chronic neuroinflammation. We isolated aggregates from postmortem hippocampi of ADRD patients, heart-disease patients, and age-matched controls. Aggregates, characterized by high-resolution proteomics (with or without crosslinking), were significantly elevated in heart-disease and ADRD hippocampi. Hexokinase-1 (HK1) and 14-3-3G/γ proteins, previously implicated in neuronal signaling and neurodegeneration, are especially enriched in ADRD and heart-disease aggregates vs. controls (each P<0.008), and their interaction was implied by extensive crosslinking in both disease groups. Screening the hexokinase-1::14-3-3G interface with FDA-approved drug structures predicted strong affinity for ezetimibe, a benign cholesterol-lowering medication. Diverse cultured human-cell and whole-nematode models of ADRD aggregation showed that this drug potently disrupts HK1::14-3-3G adhesion, reduces disease-associated aggregation, and activates autophagy. Mining clinical databases supports drug reduction of ADRD risk, decreasing it to 0.14 overall (P<0.0001; 95% C.I. 0.06-0.34), and <0.12 in high-risk heart-disease subjects (P<0.006). These results suggest that drug disruption of the 14-3-3G::HK1 interface blocks an early "lynchpin" adhesion, prospectively reducing aggregate accrual and progression of ADRD.

Keywords:  14-3-3 proteins; Aging; Alzheimer’s Disease; Hexokinase-1; Protein aggregation

DOI:  https://doi.org/10.59368/agingbio.20240028
Cells. 2024 Sep 07. pii: 1501. [Epub ahead of print]13(17):

HGA Triggers SAA Aggregation and Accelerates Fibril Formation in the C20/A4 Alkaptonuria Cell Model.

Pierfrancesco Mastroeni, Alfonso Trezza, Michela Geminiani, Luisa Frusciante, Anna Visibelli, Annalisa Santucci.

  Alkaptonuria (AKU) is a rare autosomal recessive metabolic disorder caused by mutations in the homogentisate 1,2-dioxygenase (HGD) gene, leading to the accumulation of homogentisic acid (HGA), causing severe inflammatory conditions. Recently, the presence of serum amyloid A (SAA) has been reported in AKU tissues, classifying AKU as novel secondary amyloidosis; AA amyloidosis is characterized by the extracellular tissue deposition of fibrils composed of fragments of SAA. AA amyloidosis may complicate several chronic inflammatory conditions, like rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, chronic infections, neoplasms, etc. Treatments of AA amyloidosis relieve inflammatory disorders by reducing SAA concentrations; however, no definitive therapy is currently available. SAA regulation is a crucial step to improve AA secondary amyloidosis treatments. Here, applying a comprehensive in vitro and in silico approach, we provided evidence that HGA is a disruptor modulator of SAA, able to enhance its polymerization, fibril formation, and aggregation upon SAA/SAP colocalization. In silico studies deeply dissected the SAA misfolding molecular pathway and SAA/HGA binding, suggesting novel molecular insights about it. Our results could represent an important starting point for identifying novel therapeutic strategies in AKU and AA secondary amyloidosis-related diseases.

Keywords:  HGA; alkaptonuria; amyloid; docking and molecular dynamics simulation; metabolic disease; molecular modeling; secondary amyloidosis; serum amyloid A; serum amyloid P

DOI:  https://doi.org/10.3390/cells13171501
Biochem Biophys Res Commun. 2024 Sep 02. pii: S0006-291X(24)01176-8. [Epub ahead of print]734 150640

Upregulation of NFE2L1 reduces ROS levels and α-synuclein aggregation caused by GBA1 knockdown.

Yajun Li, Shuxia Wen, Wanqing Xiang, Fei Shen, Nan Jiang, Jin Zhang, Duan Ma.

  Biallelic mutations in the GBA1 gene result in Gaucher disease (GD), and both patients with GD and carriers of a single GBA1 mutation have an increased susceptibility to Parkinson's disease (PD), but the underlying mechanisms of this association are not yet clear. In previous studies, we established Gba1 F213I point mutation mice and found that homozygous Gba1 F213I mutant mice died shortly after birth, while heterozygous mice could survive normally. In this study, we investigated the transcriptomic changes in the brain tissue of Gba1 F213I heterozygous mice, identifying 138 differentially expressed genes. Among them, Nfe2l1 was the most significantly downregulated gene. Inhibition or knockdown of GBA1 in BE(2)-M17 cells resulted in decreased expression levels of NFE2L1. Knockdown of GBA1 or NFE2L1 could lead to an elevation in intracellular aggregation of α-synuclein (α-syn) and reactive oxygen species (ROS) levels, while upregulation of NFE2L1 effectively mitigated those cellular manifestations induced by GBA1 knockdown. In summary, our in vitro results showed that upregulation of NFE2L1 may provide a therapeutic benefit for cellular phenotypes resulting from GBA1 knockdown, providing new insights for future research on GD and GBA1-associated PD.

Keywords:  GBA1; Gaucher disease; NFE2L1; Parkinson's disease

DOI:  https://doi.org/10.1016/j.bbrc.2024.150640