bims-proned Biomed News
on Proteostasis in neurodegeneration
Issue of 2024‒10‒13
twelve papers selected by
Verena Kohler, Umeå University
  1. Unraveling the Molecular Jam: How Crowding Shapes Protein Aggregation in Neurodegenerative Disorders.
  2. Conformational Enigma of TDP-43 Misfolding in Neurodegenerative Disorders.
  3. Interplay of α-Synuclein Oligomers and Endoplasmic Reticulum Stress in Parkinson'S Disease: Insights into Cellular Dysfunctions.
  4. Different charged biopolymers induce α-synuclein to form fibrils with distinct structures.
  5. Small molecule modulators of Alpha-Synuclein Aggregation and Toxicity: Pioneering an Emerging Arsenal Against Parkinson's Disease.
  6. Self-limiting multimerization of α-synuclein on membrane and its implication in Parkinson's diseases.
  7. Critical aggregation concentration and reversibility of amyloid-β (1-40) oligomers.
  8. Flavones Suppress Aggregation and Amyloid Fibril Formation of Human Lysozyme under Macromolecular Crowding Conditions.
  9. Selection of DNA aptamers that prevent the fibrillization of α-synuclein protein in cellular and mouse models.
  10. Computational Insights Into the Mechanism of EGCG's Binding and Inhibition of the TDP-43 Aggregation.
  11. Motor deficits and brain pathology in the Parkinson's disease mouse model hA53Ttg.
  12. Treatment with Tau fibrils impact Huntington's disease-related phenotypes in cell and mouse models.
  1. ACS Chem Biol. 2024 Oct 07.
    Unraveling the Molecular Jam: How Crowding Shapes Protein Aggregation in Neurodegenerative Disorders.
    Shashi Prakash Patel, Tejas Nikam, Bhargavi Sreepathi, Vijayshree S Karankar, Ankita Jaiswal, Salumuri Vamsi Vardhan, Anika Rana, Vanshu Toga, Nidhi Srivastava, Shubhini A Saraf, Saurabh Awasthi.
      Protein misfolding and aggregation are the hallmarks of neurodegenerative diseases including Huntington's disease, Parkinson's disease, Alzheimer's disease, and prion diseases. A crowded cellular environment plays a crucial role in modulating protein aggregation processes in vivo and the pathological aggregation of proteins linked to different neurodegenerative disorders. Here, we review recent studies examining the effects of various crowding agents, such as polysaccharides, polyethylene glycol, and proteins like BSA and lysozyme on the behaviors of aggregation of several amyloidogenic peptides and proteins, including amylin, huntingtin, tau, α-synuclein, prion, and amyloid-β. We also summarize how the aggregation kinetics, thermodynamic stability, and morphology of amyloid fibrils are altered significantly in the presence of crowding agents. In addition, we also discuss the molecular basis underlying the modulation of amyloidogenic aggregation, focusing on changes in the protein conformation, and the nucleation mechanism. The molecular understanding of the effects of macromolecular crowding on amyloid aggregation is essential for revealing disease pathologies and identifying possible therapeutic targets. Thus, this review offers a perspective on the complex interplay between protein aggregation and the crowded cellular environment in vivo and explains the relevance of crowding in the context of neurodegenerative disorders.
    DOI:  https://doi.org/10.1021/acschembio.4c00365
  2. ACS Omega. 2024 Oct 01. 9(39): 40286-40297
    Conformational Enigma of TDP-43 Misfolding in Neurodegenerative Disorders.
    Meenakshi Pillai, Santosh Kumar Jha.
      Misfolding and aggregation of the protein remain some of the most common phenomena observed in neurodegeneration. While there exist multiple neurodegenerative disorders characterized by accumulation of distinct proteins, what remains particularly interesting is the ability of these proteins to undergo a conformational change to form aggregates. TDP-43 is one such nucleic acid binding protein whose misfolding is associated with many neurogenerative diseases including amyotrophic lateral sclerosis (ALS) and fronto-temporal lobar degeneration (FTLD). TDP-43 protein assumes several different conformations and oligomeric states under the diseased condition. In this review, we explore the intrinsic relationship between the conformational variability of TDP-43 protein, with a particular focus on the RRM domains, and its propensity to undergo aggregation. We further emphasize the probable mechanism behind the formation of these conformations and suggest a potential diagnostic and therapeutic strategy in the context of these conformational states of the protein.
    DOI:  https://doi.org/10.1021/acsomega.4c04119
  3. Inflammation. 2024 Oct 09.
    Interplay of α-Synuclein Oligomers and Endoplasmic Reticulum Stress in Parkinson'S Disease: Insights into Cellular Dysfunctions.
    Hui Zeng, Ye Liu, Xinjie Liu, Jianwei Li, Lixuan Lu, Cheng Xue, Xiao Wu, Xinran Zhang, Zijian Zheng, Guohui Lu.
      Oligomeric forms of α-synuclein (α-syn) are critical in the formation of α-synuclein fibrils, exhibiting neurotoxic properties that are pivotal in the pathogenesis of Parkinson's disease (PD). A salient feature of this pathology is the disruption of the protein folding capacity of the endoplasmic reticulum (ER), leading to a perturbation in the ER's protein quality control mechanisms. The accumulation of unfolded or misfolded proteins instigates ER stress. However, the onset of ER stress and the consequent activation of the Unfolded Protein Response (UPR) and Endoplasmic Reticulum-Associated Degradation (ERAD) pathways do not merely culminate in apoptosis when they fail to restore cellular homeostasis. More critically, this condition initiates a cascade of reactions involving ER-related structures and organelles, resulting in multifaceted cellular damage and, potentially, a feedback loop that precipitates neuroinflammation. In this review, we elucidate the interplay between UPR and ERAD, as well as the intricate crosstalk among the ER and other organelles such as mitochondria, lysosomes, and the Golgi apparatus, underscoring their roles in the neurodegenerative process.
    Keywords:  Alpha-synuclein; Autophagy; Endoplasmic Reticulum Stress; Mitochondria; PD
    DOI:  https://doi.org/10.1007/s10753-024-02156-6
  4. J Biol Chem. 2024 Oct 05. pii: S0021-9258(24)02364-0. [Epub ahead of print] 107862
    Different charged biopolymers induce α-synuclein to form fibrils with distinct structures.
    Yuxuan Yao, Qinyue Zhao, Youqi Tao, Kaien Liu, Tianyi Cao, Zipeng Chen, Cong Liu, WeiDong Le, Jing Zhao, Dan Li, Wenyan Kang.
      The aggregation of α-synuclein (α-syn) into amyloid fibrils, a key process in the development of Parkinson's disease (PD) and other synucleinopathies, is influenced by a range of factors such as charged biopolymers, chaperones, and metabolites. However, the specific impacts of different biopolymers on α-syn fibril structure are not well understood. In our work, we found that different polyanions and polycations, such as polyphosphate (polyP), polyuridine (polyU), and polyamines (including putrescine, spermidine, and spermine), markedly altered the fibrillation kinetics of α-syn in vitro. Furthermore, seeding assay revealed distinct cross-seeding capacities across different biopolymer-induced α-syn fibrils, suggesting the formation of structurally distinct strains under different conditions. Utilizing cryo-electron microscopy (cryo-EM), we further examined the detailed structural configuration of α-syn fibrils formed in the presence of these biopolymers. Notably, we found that while polyamines do not change the atomic structure of α-syn fibrils, polyU and polyP induce the formation of distinct amyloid fibrils, exhibiting a range of structural polymorphs. Our work offers valuable insights into how various charged biopolymers affect the aggregation process and the resultant structures of α-syn fibrils, thereby enhancing our understanding of the structural variations in α-syn fibrils across different pathological conditions.
    DOI:  https://doi.org/10.1016/j.jbc.2024.107862
  5. Ageing Res Rev. 2024 Oct 08. pii: S1568-1637(24)00356-8. [Epub ahead of print] 102538
    Small molecule modulators of Alpha-Synuclein Aggregation and Toxicity: Pioneering an Emerging Arsenal Against Parkinson's Disease.
    Ishfaq Ahmad Ahanger, Tanveer Ali Dar.
      Parkinson's disease (PD) is primarily characterized by loss of dopaminergic neurons in the substantia nigra pars compacta region of the brain and accumulation of aggregated forms of alpha-synuclein (α-Syn), an intrinsically disordered protein, in the form of Lewy Bodies and Lewy Neurites. Substantial evidences point to the aggregated/fibrillar forms of α-Syn as a central event in PD pathogenesis, underscoring the modulation of α-Syn aggregation as a promising strategy for PD treatment. Consequently, numerous anti-aggregation agents, spanning from small molecules to polymers, have been scrutinized for their potential to mitigate α-Syn aggregation and its associated toxicity. Among these, small molecule modulators like osmoprotectants, polyphenols, cellular metabolites, metals, and peptides have emerged as promising candidates with significant potential in PD management. This article offers a comprehensive overview of the effects of these small molecule modulators on the aggregation propensity and associated toxicity of α-Syn and its PD-associated mutants. It serves as a valuable resource for identifying and developing potent, non-invasive, non-toxic, and highly specific small molecule-based therapeutic arsenal for combating PD. Additionally, it raises pertinent questions aimed at guiding future research endeavours in the field of α-Syn aggregation remodelling.
    Keywords:  aggregation; anti-aggregation agents, cellular metabolites; osmolytes; protein misfolding
    DOI:  https://doi.org/10.1016/j.arr.2024.102538
  6. Sci Adv. 2024 Oct 11. 10(41): eado4893
    Self-limiting multimerization of α-synuclein on membrane and its implication in Parkinson's diseases.
    Dong-Fei Ma, Shenqing Zhang, Si-Yao Xu, Zi Huang, Yuanxiao Tao, Feiyang Chen, Shengnan Zhang, Dan Li, Tongsheng Chen, Cong Liu, Ming Li, Ying Lu.
      α-Synuclein (α-syn), a crucial molecule in Parkinson's disease (PD), is known for its interaction with lipid membranes, which facilitates vesicle trafficking and modulates its pathological aggregation. Deciphering the complexity of the membrane-binding behavior of α-syn is crucial to understand its functions and the pathology of PD. Here, we used single-molecule imaging to show that α-syn forms multimers on lipid membranes with huge intermultimer distances. The multimers are characterized by self-limiting growth, manifesting in concentration-dependent exchanges of monomers, which are fast at micromolar concentrations and almost stop at nanomolar concentrations. We further uncovered movement patterns of α-syn's occasional trapping on membranes, which may be attributed to sparse lipid packing defects. Mutations such as E46K and E35K may disrupt the limit on the growth, resulting in larger multimers and accelerated amyloid fibril formation. This work emphasizes sophisticated regulation of α-syn multimerization on membranes as a critical underlying factor in the PD pathology.
    DOI:  https://doi.org/10.1126/sciadv.ado4893
  7. Arch Biochem Biophys. 2024 Oct 09. pii: S0003-9861(24)00301-1. [Epub ahead of print] 110179
    Critical aggregation concentration and reversibility of amyloid-β (1-40) oligomers.
    Sara Illodo, Wajih Al-Soufi, Mercedes Novo.
      Amyloid-beta (Aβ) aggregation is a critical factor in the pathogenesis of Alzheimer's disease, with distinct aggregation behaviours observed between its isoforms Amyloid-β 1-40 (Aβ40) and 1-42 (Aβ42). In this study, we investigated the aggregation properties of Aβ40 using fluorescence correlation spectroscopy (FCS) and detailed data analysis. Our results reveal that Aβ40 undergoes a two-step cooperative aggregation process. The first step, characterized by a critical aggregation concentration (cac) of 0.5 ± 0.3 μM, results in the formation of metastable oligomers of 5 to 25 monomers and stable oligomers of 50 to 100 monomers, with less than 10% of the amyloid aggregated. The second step, with a cac of 18.9 ± 2.2 μM, leads to the formation of much larger aggregates, consistent with protofibrils, and approximately 50% aggregated amyloid. Notably, the cac for Aβ40 is significantly higher, and the fraction of aggregated amyloid is much lower compared to Aβ42, indicating a lower propensity for aggregation. Additionally, our findings suggest that Aβ40 early oligomers are reversible upon dilution, albeit with a kinetic barrier to disaggregation. These insights into the aggregation mechanisms of Aβ40 enhance our understanding of its role in Alzheimer's disease and may inform therapeutic strategies targeting amyloid aggregation.
    Keywords:  Amyloid-β 1-40; amyloid aggregation; fluorescence correlation spectroscopy
    DOI:  https://doi.org/10.1016/j.abb.2024.110179
  8. Biochemistry. 2024 Oct 09.
    Flavones Suppress Aggregation and Amyloid Fibril Formation of Human Lysozyme under Macromolecular Crowding Conditions.
    Shabnam, Rajiv Bhat.
      The crowded milieu of a biological cell significantly impacts protein aggregation and interactions. Understanding the effects of macromolecular crowding on the aggregation and fibrillation of amyloidogenic proteins is crucial for the treatment of many amyloid-related disorders. Most in vitro studies of protein amyloid formation and its inhibition by small molecules are conducted in dilute buffers, which do not mimic the complexity of the cellular environment. In this study, we used PEGs to simulate macromolecular crowding and examined the inhibitory effects of flavones DHF, baicalein, and luteolin on human lysozyme (HuL) aggregation at pH 2. Naturally occurring flavones have been effective inhibitors of amyloid formation in some proteins. Our findings indicate that while flavones inhibit HuL aggregation and fibrillation in dilute buffer solutions, complete inhibition is observed with a combination of flavones and PEGs, as shown by ThT fluorescence, light scattering, TEM, and AFM studies. The species formed in the presence of PEG 8000 and flavones were less hydrophobic, less toxic, and α-helix-rich compared to control samples, which were hydrophobic and β-sheet-rich, as demonstrated by ANS hydrophobicity, MTT assay, and CD spectroscopy. Fluorescence titration studies of flavones with HuL showed a significant increase in binding constant values under crowding conditions. These findings highlight the importance of macromolecular crowding in modulating protein aggregation and amyloid inhibition. Further studies using disease-causing mutants of HuL and other amyloidogenic proteins are needed to explore the role of macromolecular crowding in small-molecule-mediated modulation and inhibition of protein aggregation and amyloid formation.
    DOI:  https://doi.org/10.1021/acs.biochem.4c00362
  9. Mol Ther Nucleic Acids. 2024 Sep 10. 35(3): 102251
    Selection of DNA aptamers that prevent the fibrillization of α-synuclein protein in cellular and mouse models.
    Erin M McConnell, Dennis Chan, Katelyn Ventura, Joshua P Callahan, Kathryn Harris, Vernon H Hunt, Spencer Boisjoli, Daniel Knight, Evan T Monk, Matthew R Holahan, Maria C DeRosa.
      A neuropathological hallmark of Parkinson's disease (PD) is the aggregation and spreading of misfolded α-synuclein (αSyn) protein. In this study, a selection method was developed to identify aptamers that showed affinity for monomeric αSyn and inhibition of αSyn aggregation. Aptamer a-syn-1 exhibited strong inhibition of αSyn aggregation in vitro by transmission electron microscopy and Thioflavin T fluorescence. A-syn-1-treated SH-SY5Y cells incubated with pre-formed fibrils (PFFs) showed less intracellular aggregation of αSyn in comparison with a scrambled oligonucleotide control, as observed with fluorescent microscopy. Systemic delivery of a-syn-1 to the brain was achieved using a liposome vehicle and confirmed with fluorescence microscopy and qPCR. Transgenic mice overexpressing the human A53T variant of αSyn protein were injected with a-syn-1 loaded liposomes at 5 months of age both acutely (single intraperitoneal [i.p.] injection) and repeatedly (5 i.p. injections over 5 days). Western blot protein quantification revealed that both acute and repeated injections of a-syn-1 decreased levels of the aggregated form of αSyn in the transgenic mice in the prefrontal cortex, caudate, and substania nigra (SNc). These results provide in vitro and in vivo evidence that a-syn-1 can inhibit pathological αSyn aggregation and may have implications in treatment strategies to target dysregulation in PD.
    Keywords:  MT: Oligonucleotides: Therapies and Applications; Parkinson’s disease; SELEX; SH-SY5Y cells; aptamer; fibrillization; inhibitor; α-synuclein
    DOI:  https://doi.org/10.1016/j.omtn.2024.102251
  10. Chem Biol Drug Des. 2024 Oct;104(4): e14640
    Computational Insights Into the Mechanism of EGCG's Binding and Inhibition of the TDP-43 Aggregation.
    Vini D Meshram, Ramkumar Balaji, Preethi Saravanan, Yashashwini Subbamanda, Waghela Deeksha, Akarsh Bajpai, Himanshu Joshi, Anamika Bhargava, Basant K Patel.
      Misfolding and aggregation of TAR DNA-binding protein, TDP-43, is linked to devastating proteinopathies such as ALS. Therefore, targeting TDP-43's aggregation is significant for therapeutics. Recently, green tea polyphenol, EGCG, was observed to promote non-toxic TDP-43 oligomer formation disallowing TDP-43 aggregation. Here, we investigated if the anti-aggregation effect of EGCG is mediated via EGCG's binding to TDP-43. In silico molecular docking and molecular dynamics (MD) simulation suggest a strong binding of EGCG with TDP-43's aggregation-prone C-terminal domain (CTD). Three replicas, each having 800 ns MD simulation of the EGCG-TDP-43-CTD complex, yielded a high negative binding free energy (ΔG) inferring a stable complex formation. Simulation snapshots show that EGCG forms close and long-lasting contacts with TDP-43's Phe-313 and Ala-341 residues, which were previously identified for monomer recruitment in CTD's aggregation. Notably, stable physical interactions between TDP-43 and EGCG were also detected in vitro using TTC staining and isothermal titration calorimetry which revealed a high-affinity binding site of EGCG on TDP-43 (Kd, 7.8 μM; ΔG, -6.9 kcal/mol). Additionally, TDP-43 co-incubated with EGCG was non-cytotoxic when added to HEK293 cells. In summary, EGCG's binding to TDP-43 and blocking of residues important for aggregation can be a possible mechanism of its anti-aggregation effects on TDP-43.
    Keywords:  ALS; EGCG; TDP‐43 misfolding; cytotoxicity; isothermal titration calorimetry; molecular dynamics simulation; oligomers
    DOI:  https://doi.org/10.1111/cbdd.14640
  11. Front Neurosci. 2024 ;18 1462041
    Motor deficits and brain pathology in the Parkinson's disease mouse model hA53Ttg.
    Livia Breznik, Magdalena Daurer, Roland Rabl, Tina Loeffler, Estibaliz Etxeberria-Rekalde, Joerg Neddens, Stefanie Flunkert, Manuela Prokesch.
      Background: Parkinson's disease (PD) is a debilitating neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons and the accumulation of α-synuclein (α-syn) aggregates. The A53T missense point mutation occurs in autosomal dominant familial PD and has been found to promote the aggregation of α-syn. To investigate the role of the A53T mutation in PD, researchers have developed various mouse models with this mutation.Objective: We therefore conducted a comprehensive characterization of the tg(THY1-SNCA*A53T)M53Sud mouse model (hA53Ttg mice) for its motor and pathological features.
    Methods: hA53Ttg mice were tested for motor impairments in a series of motor tests at 2, 4 or 6 months of age. Human α-syn and α-syn pSer129, as well as GFAP and Iba1 signal were labeled and quantified in the cortex, hippocampus, and brainstem. Neurofilament light chain (NF-L) levels were measured in the cerebrospinal fluid (CSF) and plasma. Ex vivo analyses were performed at the age of 2, 4, 6, and 10 months.
    Results: Behavioral tests revealed early muscle weakness and motor impairments that progressed with age. Immunohistochemical analyses demonstrated elevated levels of human α-syn and α-syn pSer129 in all evaluated brain regions. α-syn pSer129 labeling further revealed fiber-like structures in the cortex of older animals. Neuroinflammation was observed in an age-dependent manner. Biochemical evaluation revealed elevated NF-L levels in the plasma and CSF. Overall, our findings highlight the value of hA53Ttg mice in modeling PD-associated pathologies that closely resemble those observed in PD patients.
    Conclusion: Our results thus suggest that hA53Ttg mice are a useful tool for studying the underlying mechanisms of PD.
    Keywords:  Parkinson’s disease; motor skills; neurodegeneration; neuroinflammation; transgenic mouse; α-synuclein
    DOI:  https://doi.org/10.3389/fnins.2024.1462041
  12. Neurobiol Dis. 2024 Oct 08. pii: S0969-9961(24)00296-1. [Epub ahead of print] 106696
    Treatment with Tau fibrils impact Huntington's disease-related phenotypes in cell and mouse models.
    Shireen Salem, Melanie Alpaugh, Martine Saint-Pierre, Flavia Natale Alves-Martins-Borba, Catalina Cerquera-Cleves, Mado Lemieux, Soki Bradel Ngonza-Nito, Paul De Koninck, Ronald Melki, Francesca Cicchetti.
      There is now compelling evidence for the presence of pathological forms of Tau in tissues of both patients and animal models of Huntington's disease (HD). While the root cause of this illness is a mutation within the huntingtin gene, a number of studies now suggest that HD could also be considered a secondary tauopathy. However, the contributory role of Tau in the pathogenesis and pathophysiology of this condition, as well as its implications in cellular toxicity and consequent behavioral impairments are largely unknown. We therefore performed intracerebral stereotaxic injections of recombinant human Tau monomers and fibrils into the knock-in zQ175 mouse model of HD. Tau fibrils induced cognitive and anxiety-like phenotypes predominantly in zQ175 mice and increased the number and size of insoluble mutant huntingtin (mHTT) aggregates in the brains of treated animals. To better understand the putative mechanisms through which Tau could initiate and/or contribute to pathology, we incubated StHdh striatal cells, a cellular model of HD, with the different Tau forms and evaluated the effects on cell functionality and heat shock proteins Hsp70 and Hsp90. Calcium imaging experiments showed functional impairments of HD StHdh cells following treatment with Tau fibrils, as well as significant changes to the levels of both heat shock proteins which were found trapped within mHTT aggregates. The accumulation of Hsp70 and 90 within aggregates was also present in mouse tissue which suggests that alteration of molecular chaperone-dependent protein quality control may influence aggregation, implicating proteostasis in the mHTT-Tau interplay.
    Keywords:  Animal behavior; Heat shock proteins; Huntingtin aggregation; Mutant huntingtin protein; zQ175
    DOI:  https://doi.org/10.1016/j.nbd.2024.106696
This page is being maintained by Thomas Krichel. It was last updated on 2024‒10‒18 at 15:57.