bims-proned 2024-06-30 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2024‒06‒30
eleven papers selected by
Verena Kohler, Umeå University

A Perspective on Interdicting in Protein Misfolding for Therapeutic Drug Design: Modulating the Formation of Nonlocal Contacts in α-Synuclein as a Strategy against Parkinson's Disease.
Role of Tau Protein in Neurodegenerative Diseases and Development of Its Targeted Drugs: A Literature Review.
α-Synuclein Oligomers Displace Monomeric α-Synuclein from Lipid Membranes.
Primary Nucleation of Polymorphic α-Synuclein Dimers Depends on Copper Concentrations and Definite Copper-Binding Site.
A hydrophobic core stabilizes the residual structure in the RRM2 intermediate state of the ALS-linked protein TDP-43.
Targeting amyloid proteins for clinical diagnosis of neurodegenerative diseases.
Accumulation of Intracellular Protein Advanced Glycation End Products Alters Cellular Homeostasis for Protein Clearance in Pancreatic Ductal Epithelial Cells.
Aging and neurodegeneration: From molecular mechanisms to therapeutic interventions.
Promising Molecular Architectures for Two-Photon Probes in the Diagnosis of α-Synuclein Aggregates.
Reviewing the Structure-Function Paradigm in Polyglutamine Disorders: A Synergistic Perspective on Theoretical and Experimental Approaches.
Effects of selegiline on neuronal autophagy involving α-synuclein secretion.

J Phys Chem B. 2024 Jun 28.

A Perspective on Interdicting in Protein Misfolding for Therapeutic Drug Design: Modulating the Formation of Nonlocal Contacts in α-Synuclein as a Strategy against Parkinson's Disease.

Fernando Bergasa-Caceres, Herschel A Rabitz.

In recent work we proposed that interdiction in the earliest contact-formation events along the folding pathway of key viral proteins could provide a novel avenue for therapeutic drug design. In this Perspective we explore the potential applicability of the protein folding interdiction strategy in the realm of neurodegenerative diseases with a specific focus on synucleinopathies. In order to fulfill this goal we review the interdiction proposal and its practical challenges, and we present new results concerning design strategies for possible peptide drugs that could be useful in preventing α-synuclein aggregation.

DOI: https://doi.org/10.1021/acs.jpcb.3c07519
Molecules. 2024 Jun 13. pii: 2812. [Epub ahead of print]29(12):

Role of Tau Protein in Neurodegenerative Diseases and Development of Its Targeted Drugs: A Literature Review.

Jiakai Yang, Weijia Zhi, Lifeng Wang.

  Tau protein is a microtubule-associated protein that is widely distributed in the central nervous system and maintains and regulates neuronal morphology and function. Tau protein aggregates abnormally and forms neurofibrillary tangles in neurodegenerative diseases, disrupting the structure and function of neurons and leading to neuronal death, which triggers the initiation and progression of neurological disorders. The aggregation of tau protein in neurodegenerative diseases is associated with post-translational modifications, which may affect the hydrophilicity, spatial conformation, and stability of tau protein, promoting tau protein aggregation and the formation of neurofibrillary tangles. Therefore, studying the role of tau protein in neurodegenerative diseases and the mechanism of aberrant aggregation is important for understanding the mechanism of neurodegenerative diseases and finding therapeutic approaches. This review describes the possible mechanisms by which tau protein promotes neurodegenerative diseases, the post-translational modifications of tau protein and associated influencing factors, and the current status of drug discovery and development related to tau protein, which may contribute to the development of new therapeutic approaches to alleviate or treat neurodegenerative diseases.

Keywords:  neurodegenerative diseases; phosphorylation; post-translational modification; tau protein; therapeutic drugs

DOI:  https://doi.org/10.3390/molecules29122812
ACS Nano. 2024 Jun 25.

α-Synuclein Oligomers Displace Monomeric α-Synuclein from Lipid Membranes.

Greta Šneiderienė, Magdalena A Czekalska, Catherine K Xu, Akhila K Jayaram, Georg Krainer, William E Arter, Quentin A E Peter, Marta Castellana-Cruz, Kadi Liis Saar, Aviad Levin, Thomas Mueller, Sebastian Fiedler, Sean R A Devenish, Heike Fiegler, Janet R Kumita, Tuomas P J Knowles.

  Parkinson's disease (PD) is an increasingly prevalent and currently incurable neurodegenerative disorder linked to the accumulation of α-synuclein (αS) protein aggregates in the nervous system. While αS binding to membranes in its monomeric state is correlated to its physiological role, αS oligomerization and subsequent aberrant interactions with lipid bilayers have emerged as key steps in PD-associated neurotoxicity. However, little is known of the mechanisms that govern the interactions of oligomeric αS (OαS) with lipid membranes and the factors that modulate such interactions. This is in large part due to experimental challenges underlying studies of OαS-membrane interactions due to their dynamic and transient nature. Here, we address this challenge by using a suite of microfluidics-based assays that enable in-solution quantification of OαS-membrane interactions. We find that OαS bind more strongly to highly curved, rather than flat, lipid membranes. By comparing the membrane-binding properties of OαS and monomeric αS (MαS), we further demonstrate that OαS bind to membranes with up to 150-fold higher affinity than their monomeric counterparts. Moreover, OαS compete with and displace bound MαS from the membrane surface, suggesting that disruption to the functional binding of MαS to membranes may provide an additional toxicity mechanism in PD. These findings present a binding mechanism of oligomers to model membranes, which can potentially be targeted to inhibit the progression of PD.

Keywords:  Parkinson’s disease; aggregation; lipids; membranes; oligomers; α-synuclein

DOI:  https://doi.org/10.1021/acsnano.3c10889
Biomolecules. 2024 May 26. pii: 627. [Epub ahead of print]14(6):

Primary Nucleation of Polymorphic α-Synuclein Dimers Depends on Copper Concentrations and Definite Copper-Binding Site.

Carmia Blacher, Karina Abramov-Harpaz, Yifat Miller.

  The primary nucleation process of α-synuclein (AS) that forms toxic oligomeric species is the early stage of the pathological cause of Parkinson's disease. It is well-known that copper influences this primary nucleation process. While significant efforts have been made to solve the structures of polymorphic AS fibrils, the structures of AS oligomers and the copper-bound AS oligomers at the molecular level and the effect of copper concentrations on the primary nucleation are elusive. Here, we propose and demonstrate new molecular mechanism pathways of primary nucleation of AS that are tuned by distinct copper concentrations and by a specific copper-binding site. We present the polymorphic AS dimers bound to different copper-binding sites at the atomic resolution in high- and low-copper concentrations, using extensive molecular dynamics simulations. Our results show the complexity of the primary nucleation pathways that rely on the copper concentrations and the copper binding site. From a broader perspective, our study proposes a new strategy to control the primary nucleation of other toxic amyloid oligomers in other neurodegenerative diseases.

Keywords:  Parkinson’s disease; amyloids; metal ions; neurodegenerative diseases; oligomers; polymorphism; protein aggregation; self-assembly; α-synuclein

DOI:  https://doi.org/10.3390/biom14060627
bioRxiv. 2024 Jun 12. pii: 2024.06.12.598648. [Epub ahead of print]

A hydrophobic core stabilizes the residual structure in the RRM2 intermediate state of the ALS-linked protein TDP-43.

Brian C Mackness, Brittany R Morgan, Laura M Deveau, Sagar V Kathuria, Jill A Zitzewitz, Francesca Massi.

Folding intermediates mediate both protein folding and the misfolding and aggregation observed in human diseases, including amyotrophic lateral sclerosis (ALS), and are prime targets for therapeutic interventions. In this study, we identified the core nucleus of structure for a folding intermediate in the second RNA recognition motif (RRM2) of the ALS-linked RNA-binding protein, TDP-43, using a combination of experimental and computational approaches. Urea equilibrium unfolding studies revealed that the RRM2 intermediate state consists of collapsed residual secondary structure localized to the N-terminal half of RRM2, while the C-terminus is largely disordered. Steered molecular dynamics simulations and mutagenesis studies yielded key stabilizing hydrophobic contacts that, when mutated to alanine, severely disrupt the overall fold of RRM2. In combination, these findings suggest a role for this RRM intermediate in normal TDP-43 function as well as serving as a template for misfolding and aggregation through the low stability and non-native secondary structure.

DOI: https://doi.org/10.1101/2024.06.12.598648
Fundam Res. 2023 Jul;3(4): 505-519

Targeting amyloid proteins for clinical diagnosis of neurodegenerative diseases.

Shenqing Zhang, Hui Dong, Jiang Bian, Dan Li, Cong Liu.

  Abnormal aggregation and accumulation of pathological amyloid proteins such as amyloid-β, Tau, and α-synuclein play key pathological roles and serve as histological hallmarks in different neurodegenerative diseases (NDs) such as Alzheimer's disease (AD) and Parkinson's disease (PD). In addition, various post-translational modifications (PTMs) have been identified on pathological amyloid proteins and are subjected to change during disease progression. Given the central role of amyloid proteins in NDs, tremendous efforts have been made to develop amyloid-targeting strategies for clinical diagnosis and molecular classification of NDs. In this review, we summarize two major strategies for targeting amyloid aggregates, with a focus on the trials in AD diagnosis. The first strategy is a positron emission tomography (PET) scan of protein aggregation in the brain. We mainly focus on introducing the development of small-molecule PET tracers for specifically recognizing pathological amyloid fibrils. The second strategy is the detection of PTM biomarkers on amyloid proteins in cerebrospinal fluid and plasma. We discuss the pathological roles of different PTMs in diseases and how we can use the PTM profile of amyloid proteins for clinical diagnosis. Finally, we point out the potential technical challenges of these two strategies, and outline other potential strategies, as well as a combination of multiple strategies, for molecular diagnosis of NDs.

Keywords:  Alzheimer's disease; Amyloid aggregation; Biomarker; Clinical diagnosis; Neurodegenerative diseases; Positron emission tomography (PET) tracer; Post-translational modification; Tau

DOI:  https://doi.org/10.1016/j.fmre.2022.10.009
Biochemistry. 2024 Jun 28.

Accumulation of Intracellular Protein Advanced Glycation End Products Alters Cellular Homeostasis for Protein Clearance in Pancreatic Ductal Epithelial Cells.

Lakmini Senavirathna, Christopher Hasapes, Ru Chen, Sheng Pan.

Protein advanced glycation end products (AGEs) can be formed via nonenzymatic glycation and accumulated intracellularly to disrupt cellular homeostasis for protein clearance. Here, we investigated the formation particulars of intracellular protein AGEs and sought to elucidate the molecular events implicated in the impact of cellular clearance systems. The formation and accumulation of intracellular protein AGEs increased protein aggregation and protease resistance, potentially overwhelming the ubiquitin-proteasome system (UPS). At high levels of protein AGEs, the abundance of many E3 ligases decreased and the overall ubiquitination level was reduced, all of which indicated decreased UPS activity. On the other hand, autophagy activity was stimulated, as evidenced by the upregulation of autophagy marker LC3II and important proteins in autophagosome and autolysosome formation, as well as downregulation of mTOR. Understanding the functional impacts of intracellular protein AGEs on the UPS and autophagy could pave the way for the future development of pharmaceutical agents targeting AGE-related diseases.

DOI: https://doi.org/10.1021/acs.biochem.4c00250
J Neurochem. 2024 Jun 22.

Aging and neurodegeneration: From molecular mechanisms to therapeutic interventions.

Tiago Fleming Outeiro, Patricia S Brocardo, Daniel P Gelain.

  Protein aggregation is a common age-associated process and can be a pathological hallmark of various neurodegenerative conditions, possibly because of an age-associated decline in the activity of components of the proteostasis network. The specific molecular drivers of protein aggregation in certain cell types are not well understood, posing tremendous challenges to current research aimed at devising strategies to treat neurodegenerative diseases. This preface introduces the special issue "Aging and Neurodegeneration: from molecular mechanisms to therapeutic interventions," featuring articles that assess the drivers of pathology in the aging cell, including oxidative stress, protein glycation/aggregation, and mitochondrial impairment.

Keywords:  aging; neurodegeneration; neuronal plasticity; protein aggregation; therapeutics

DOI:  https://doi.org/10.1111/jnc.16163
Molecules. 2024 Jun 13. pii: 2817. [Epub ahead of print]29(12):

Promising Molecular Architectures for Two-Photon Probes in the Diagnosis of α-Synuclein Aggregates.

Stefania Porcu, Riccardo Corpino, Carlo Maria Carbonaro, Pier Carlo Ricci, Attilio Vittorio Vargiu, Anna Laura Sanna, Giuseppe Sforazzini, Daniele Chiriu.

  The abnormal deposition of protein in the brain is the central factor in neurodegenerative disorders (NDs). These detrimental aggregates, stemming from the misfolding and subsequent irregular aggregation of α-synuclein protein, are primarily accountable for conditions such as Parkinson's disease, Alzheimer's disease, and dementia. Two-photon-excited (TPE) probes are a promising tool for the early-stage diagnosis of these pathologies as they provide accurate spatial resolution, minimal intrusion, and the ability for prolonged observation. To identify compounds with the potential to function as diagnostic probes using two-photon techniques, we explore three distinct categories of compounds: Hydroxyl azobenzene (AZO-OH); Dicyano-vinyl bithiophene (DCVBT); and Tetra-amino phthalocyanine (PcZnNH2). The molecules were structurally and optically characterized using a multi-technique approach via UV-vis absorption, Raman spectroscopy, three-dimensional fluorescence mapping (PLE), time-resolved photoluminescence (TRPL), and pump and probe measurements. Furthermore, quantum chemical and molecular docking calculations were performed to provide insights into the photophysical properties of the compounds as well as to assess their affinity with the α-synuclein protein. This innovative approach seeks to enhance the accuracy of in vivo probing, contributing to early Parkinson's disease (PD) detection and ultimately allowing for targeted intervention strategies.

Keywords:  early PD detection; in vivo probing; molecular docking; targeted intervention strategies; two-photon-excited (TPE) probes

DOI:  https://doi.org/10.3390/molecules29122817
Int J Mol Sci. 2024 Jun 20. pii: 6789. [Epub ahead of print]25(12):

Reviewing the Structure-Function Paradigm in Polyglutamine Disorders: A Synergistic Perspective on Theoretical and Experimental Approaches.

Nastasia Sanda Moldovean-Cioroianu.

  Polyglutamine (polyQ) disorders are a group of neurodegenerative diseases characterized by the excessive expansion of CAG (cytosine, adenine, guanine) repeats within host proteins. The quest to unravel the complex diseases mechanism has led researchers to adopt both theoretical and experimental methods, each offering unique insights into the underlying pathogenesis. This review emphasizes the significance of combining multiple approaches in the study of polyQ disorders, focusing on the structure-function correlations and the relevance of polyQ-related protein dynamics in neurodegeneration. By integrating computational/theoretical predictions with experimental observations, one can establish robust structure-function correlations, aiding in the identification of key molecular targets for therapeutic interventions. PolyQ proteins' dynamics, influenced by their length and interactions with other molecular partners, play a pivotal role in the polyQ-related pathogenic cascade. Moreover, conformational dynamics of polyQ proteins can trigger aggregation, leading to toxic assembles that hinder proper cellular homeostasis. Understanding these intricacies offers new avenues for therapeutic strategies by fine-tuning polyQ kinetics, in order to prevent and control disease progression. Last but not least, this review highlights the importance of integrating multidisciplinary efforts to advancing research in this field, bringing us closer to the ultimate goal of finding effective treatments against polyQ disorders.

Keywords:  CAG expansion; aggregation; neurodegeneration; polyglutamine disorders; protein dynamics; protein function; structure–function

DOI:  https://doi.org/10.3390/ijms25126789
Biochem Biophys Res Commun. 2024 Jun 14. pii: S0006-291X(24)00803-9. [Epub ahead of print]725 150267

Effects of selegiline on neuronal autophagy involving α-synuclein secretion.

Kensuke Kakiuchi, Yoshitsugu Nakamura, Taiki Sawai, Shigeki Arawaka.

  Cell-to-cell transmission of α-synuclein (α-syn) pathology underlies the spread of neurodegeneration in Parkinson's disease. α-Syn secretion is an important factor in the transmission of α-syn pathology. However, it is unclear how α-syn secretion is therapeutically modulated. Here, we investigated effects of monoamine oxidase (MAO)-B inhibitor selegiline on α-syn secretion. Treatment with selegiline promoted α-syn secretion in mouse primary cortical neuron cultures, and this increase was kept under glial cell-eliminated condition by Ara-C. Selegiline-induced α-syn secretion was blocked by cytosolic Ca2+ chelator BAPTA-AM in primary neurons. Selegiline-induced α-syn secretion was retained in MAOA siRNA knockdown, whereas it was abrogated by ATG5 knockdown in SH-SY5Y cells. Selegiline increased LC3-II generation with a reduction in intracellular p62/SQSTM1 levels in primary neurons. The increase in LC3-II generation was blocked by co-treatment with BAPTA-AM in primary neurons. Additionally, fractionation experiments showed that selegiline-induced α-syn secretion occurred in non-extracellular vesicle fractions of primary neurons and SH-SY5Y cells. Collectively, these findings show that selegiline promotes neuronal autophagy involving secretion of non-exosomal α-syn via a change of cytosolic Ca2+ levels.

Keywords:  Autophagy; Extracellular vesicle; Neurons; Secretion; Selegiline; α-Synuclein

DOI:  https://doi.org/10.1016/j.bbrc.2024.150267