bims-proned Biomed News
on Proteostasis in neurodegeneration
Issue of 2024–12–01
eightteen papers selected by
Verena Kohler, Umeå University
  1. Targeting Protein Misfolding and Aggregation as a Therapeutic Perspective in Neurodegenerative Disorders.
  2. α-Synuclein ubiquitination - functions in proteostasis and development of Lewy bodies.
  3. Technique for Intranasal Administration of α-Synuclein Aggregates.
  4. Co-Aggregation of TDP-43 with Other Pathogenic Proteins and Their Co-Pathologies in Neurodegenerative Diseases.
  5. Imidazo[2,1-b][1,3]thiazine Derivatives as Potential Modulators of Alpha-Synuclein Amyloid Aggregation.
  6. Angiotensin type-1 receptor autoantibodies promote alpha-synuclein aggregation in dopaminergic neurons.
  7. Prion-like Spreading of Disease in TDP-43 Proteinopathies.
  8. Modulation of Biological Membranes Using Small-Molecule Compounds to Counter Toxicity Caused by Amyloidogenic Proteins.
  9. Hydrogen-Deuterium Exchange Mass Spectrometry Reveals Mechanistic Insights into RNA Oligonucleotide-Mediated Inhibition of TDP-43 Aggregation.
  10. Young rat microbiota extracts strongly inhibit fibrillation of α-synuclein and protect neuroblastoma cells and zebrafish against α-synuclein toxicity.
  11. Divergent and Convergent TMEM106B Pathology in Murine Models of Neurodegeneration and Human Disease.
  12. Seeding activity of skin misfolded tau as a biomarker for tauopathies.
  13. Erucin, a Natural Isothiocyanate, Prevents Polyglutamine-Induced Toxicity in Caenorhabditis elegans via aak-2/AMPK and daf-16/FOXO Signaling.
  14. Discovery of penicillic acid as a chemical probe against tau aggregation in Alzheimer's disease.
  15. Detecting and Tracking β-Amyloid Oligomeric Forms and Dynamics In Vitro by a High-Sensitivity Fluorescent-Based Assay.
  16. Seeding-competent TDP-43 persists in human patient and mouse muscle.
  17. SARS-CoV-2 Infection and Alpha-Synucleinopathies: Potential Links and Underlying Mechanisms.
  18. Liquid-liquid phase separation of tau and α-synuclein: A new pathway of overlapping neuropathologies.
  1. Int J Mol Sci. 2024 Nov 20. pii: 12448. [Epub ahead of print]25(22):
    Targeting Protein Misfolding and Aggregation as a Therapeutic Perspective in Neurodegenerative Disorders.
    Marta Sidoryk-Węgrzynowicz, Kamil Adamiak, Lidia Strużyńska.
      The abnormal deposition and intercellular propagation of disease-specific protein play a central role in the pathogenesis of many neurodegenerative disorders. Recent studies share the common observation that the formation of protein oligomers and subsequent pathological filaments is an essential step for the disease. Synucleinopathies such as Parkinson's disease (PD), dementia with Lewy bodies (DLB) or multiple system atrophy (MSA) are neurodegenerative diseases characterized by the aggregation of the α-synucleinprotein in neurons and/or in oligodendrocytes (glial cytoplasmic inclusions), neuronal loss, and astrogliosis. A similar mechanism of protein Tau-dependent neurodegeneration is a major feature of tauopathies, represented by Alzheimer's disease (AD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and Pick's disease (PD). The specific inhibition of the protein misfolding and their interneuronal spreading represents a promising therapeutic strategy against both disease pathology and progression. The most recent research focuses on finding potential applications targeting the pathological forms of proteins responsible for neurodegeneration. This review highlights the mechanisms relevant to protein-dependent neurodegeneration based on the most common disorders and describes current therapeutic approaches targeting protein misfolding and aggregation.
    Keywords:  anle138b; antibody; dynasore; epigallocatechin gallate; fulvic; neurodegeneration; protein aggregation
    DOI:  https://doi.org/10.3390/ijms252212448
  2. Front Mol Neurosci. 2024 ;17 1498459
    α-Synuclein ubiquitination - functions in proteostasis and development of Lewy bodies.
    Hung-Hsiang Ho, Simon S Wing.
      Synucleinopathies are neurodegenerative disorders characterized by the accumulation of α-synuclein containing Lewy bodies. Ubiquitination, a key post-translational modification, has been recognized as a pivotal regulator of α-synuclein's cellular dynamics, influencing its degradation, aggregation, and associated neurotoxicity. This review examines comprehensively the current understanding of α-synuclein ubiquitination and its role in the pathogenesis of synucleinopathies, particularly in the context of Parkinson's disease. We explore the molecular mechanisms responsible for α-synuclein ubiquitination, with a focus on the roles of E3 ligases and deubiquitinases implicated in the degradation process which occurs primarily through the endosomal lysosomal pathway. The review further discusses how the dysregulation of these mechanisms contributes to α-synuclein aggregation and LB formation and offers suggestions for future investigations into the role of α-synuclein ubiquitination. Understanding these processes may shed light on potential therapeutic avenues that can modulate α-synuclein ubiquitination to alleviate its pathological impact in synucleinopathies.
    Keywords:  Lewy body; Parkinson’s disease; autophagy; endosome; lysosome; proteasome; ubiquitin; α-synuclein
    DOI:  https://doi.org/10.3389/fnmol.2024.1498459
  3. J Vis Exp. 2024 Nov 08.
    Technique for Intranasal Administration of α-Synuclein Aggregates.
    Masanori Sawamura, Ryosuke Takahashi.
      Parkinson's disease (PD) is a neurodegenerative disorder characterized by the presence of Lewy bodies, which are aggregates of α-synuclein (α-Syn). Recently, the disease was proposed to develop and progress through the prion-like propagation of α-Syn aggregates from the olfactory bulb (OB) or dorsal nucleus of the vagus nerve. Although the origin of α-Syn aggregates in the OB remains unclear, their propagation from the olfactory mucosa has been recently suggested. We previously showed that intranasal administration of α-Syn aggregates in a mouse model induced α-Syn pathology in the OB of mice. In this study, we present a method of intranasal administration of α-Syn aggregates that induced α-Syn pathology in the OB of mice. Intranasal administration of α-Syn aggregates is a very simple and straightforward method, and we believe it will be a useful tool in the research for elucidating the origin of α-Syn pathology in the OB and the pathway of α-Syn propagation through the olfactory system.
    DOI:  https://doi.org/10.3791/66943
  4. Int J Mol Sci. 2024 Nov 18. pii: 12380. [Epub ahead of print]25(22):
    Co-Aggregation of TDP-43 with Other Pathogenic Proteins and Their Co-Pathologies in Neurodegenerative Diseases.
    Lei-Lei Jiang, Xiang-Le Zhang, Hong-Yu Hu.
      Pathological aggregation of a specific protein into insoluble aggregates is a common hallmark of various neurodegenerative diseases (NDDs). In the earlier literature, each NDD is characterized by the aggregation of one or two pathogenic proteins, which can serve as disease-specific biomarkers. The aggregation of these specific proteins is thought to be a major cause of or deleterious result in most NDDs. However, accumulating evidence shows that a pathogenic protein can interact and co-aggregate with other pathogenic proteins in different NDDs, thereby contributing to disease onset and progression synergistically. During the past years, more than one type of NDD has been found to co-exist in some individuals, which may increase the complexity and pathogenicity of these diseases. This article reviews and discusses the biochemical characteristics and molecular mechanisms underlying the co-aggregation and co-pathologies associated with TDP-43 pathology. The TDP-43 aggregates, as a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), can often be detected in other NDDs, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and spinocerebellar ataxia type 2 (SCA2). In many cases, TDP-43 is shown to interact and co-aggregate with multiple pathogenic proteins in vitro and in vivo. Furthermore, the co-occurrence and co-aggregation of TDP-43 with other pathogenic proteins have important consequences that may aggravate the diseases. Thus, the current viewpoint that the co-aggregation of TDP-43 with other pathogenic proteins in NDDs and their relevance to disease progression may gain insights into the patho-mechanisms and therapeutic potential of various NDDs.
    Keywords:  TDP-43 pathology; co-aggregation; co-pathology; neurodegenerative disease; pathogenic protein
    DOI:  https://doi.org/10.3390/ijms252212380
  5. ACS Chem Neurosci. 2024 Nov 27.
    Imidazo[2,1-b][1,3]thiazine Derivatives as Potential Modulators of Alpha-Synuclein Amyloid Aggregation.
    Indrė Misiu Naitė, Kamilė Mikalauskaitė, Martyna Paulauskaitė, Ru Ta Sniečkutė, Vytautas Smirnovas, Algirdas Brukštus, Mantas Žiaunys, Ieva Žutautė.
      Insoluble amyloid fibrils accumulate in the intercellular spaces of organs and tissues, leading to various amyloidosis-related disorders in the human body. Specifically, Parkinson's disease is associated with the aggregation of alpha-synuclein. However, current treatments for Parkinson's primarily focus on managing motor symptoms and slowing disease progression. Efforts to prevent and halt the progression of these diseases involve the search for small molecular compounds. In this work, we synthesized imidazo[2,1-b][1,3]thiazines in an atom-economic way by cyclization of 2-alkynylthioimidazoles using 10% AuCl as the catalyst. We identified several compounds with specific functional groups capable of both inhibiting the aggregation of alpha-synuclein and redirecting the fibril formation pathway. The investigation into how these substances function revealed that imidazo[2,1-b][1,3]thiazine derivatives can influence alpha-synuclein aggregation in several ways. They not only inhibit the primary nucleation process and maintain a balance toward nonaggregated protein states but also stabilize smaller oligomeric species of alpha-synuclein and cause the formation of fibrils with unique structures and forms. These imidazo[2,1-b][1,3]thiazines could potentially be used in developing highly efficient, small molecular weight protein aggregation inhibitors.
    Keywords:  Au catalysis; alkynes; alpha-synuclein; amyloid aggregation; cyclization; imidazoles
    DOI:  https://doi.org/10.1021/acschemneuro.4c00451
  6. Front Immunol. 2024 ;15 1457459
    Angiotensin type-1 receptor autoantibodies promote alpha-synuclein aggregation in dopaminergic neurons.
    Lucia Lage, Ana I Rodríguez-Perez, Jose L Labandeira-Garcia, Antonio Dominguez-Meijide.
      Angiotensin, through its type-1 receptor (AT1), is a major inducer of inflammation and oxidative stress, contributing to several diseases. Autoimmune processes have been involved in neurodegeneration, including Parkinson's disease (PD). AT1 autoantibodies (AT1-AA) enhance neurodegeneration and PD, which was related to increased neuronal oxidative stress and neuroinflammation. However, the effect of AT1-AA on α-synuclein aggregation, a major factor in PD progression, has not been studied. In cultures of dopaminergic neurons, we observed that AT1-AA promote aggregation of α-synuclein, as AT1-AA upregulated major mechanisms involved in the α-synuclein aggregation process such as NADPH-oxidase activation and intracellular calcium raising. The results further support the role of AT1 receptors in dopaminergic neuron degeneration, and several recent clinical studies observing the neuroprotective effects of AT1 receptor blockers.
    Keywords:  Parkinson; alpha-synuclein; angiotensin; autoimmunity; neurodegeneration; protein aggregates
    DOI:  https://doi.org/10.3389/fimmu.2024.1457459
  7. Brain Sci. 2024 Nov 09. pii: 1132. [Epub ahead of print]14(11):
    Prion-like Spreading of Disease in TDP-43 Proteinopathies.
    Emma Pongrácová, Emanuele Buratti, Maurizio Romano.
      TDP-43 is a ubiquitous nuclear protein that plays a central role in neurodegenerative disorders collectively known as TDP-43 proteinopathies. Under physiological conditions, TDP-43 is primarily localized to the nucleus, but in its pathological form it aggregates in the cytoplasm, contributing to neuronal death. Given its association with numerous diseases, particularly ALS and FTLD, the mechanisms underlying TDP-43 aggregation and its impact on neuronal function have been extensively investigated. However, little is still known about the spreading of this pathology from cell to cell. Recent research has unveiled the possibility that TDP-43 may possess prion-like properties. Specifically, misfolded TDP-43 aggregates can act as templates inducing conformational changes in native TDP-43 molecules and propagating the misfolded state across neural networks. This review summarizes the mounting and most recent evidence from in vitro and in vivo studies supporting the prion-like hypothesis and its underlying mechanisms. The prion-like behavior of TDP-43 has significant implications for diagnostics and therapeutics. Importantly, emerging strategies such as small molecule inhibitors, immunotherapies, and gene therapies targeting TDP-43 propagation offer promising avenues for developing effective treatments. By elucidating the mechanisms of TDP-43 spreading, we therefore aim to pave the way for novel therapies for TDP-43-related neurodegenerative diseases.
    Keywords:  ALS; FTLD-TDP; TDP-43; aggregation; cell-to-cell transmission; pathological spreading; prion-like; proteinopathy
    DOI:  https://doi.org/10.3390/brainsci14111132
  8. Membranes (Basel). 2024 Nov 06. pii: 231. [Epub ahead of print]14(11):
    Modulation of Biological Membranes Using Small-Molecule Compounds to Counter Toxicity Caused by Amyloidogenic Proteins.
    Raina Marie Seychell, Adam El Saghir, Neville Vassallo.
      The transition of peptides or proteins along a misfolding continuum from soluble functional states to pathological aggregates, to ultimately deposit as amyloid fibrils, is a process that underlies an expanding group of human diseases-collectively known as protein-misfolding disorders (PMDs). These include common and debilitating conditions, such as Alzheimer's disease, Parkinson's disease, and type-2 diabetes. Compelling evidence has emerged that the complex interplay between the misfolded proteins and biological membranes is a key determinant of the pathogenic mechanisms by which harmful amyloid entities are formed and exert their cytotoxicity. Most efforts thus far to develop disease-modifying treatments for PMDs have largely focused on anti-aggregation strategies: to neutralise, or prevent the formation of, toxic amyloid species. Herein, we review the critical role of the phospholipid membrane in mediating and enabling amyloid pathogenicity. We consequently propose that the development of small molecules, which have the potential to uniquely modify the physicochemical properties of the membrane and make it more resilient against damage by misfolded proteins, could provide a novel therapeutic approach in PMDs. By way of an example, natural compounds shown to intercalate into lipid bilayers and inhibit amyloid-lipid interactions, such as the aminosterols, squalamine and trodusquamine, cholesterol, ubiquinone, and select polyphenols, are discussed. Such a strategy would provide a novel approach to counter a wide range of toxic biomolecules implicit in numerous human amyloid pathologies.
    Keywords:  amyloid; lipid membranes; protein aggregation; protein-misfolding diseases; small molecules; therapeutics
    DOI:  https://doi.org/10.3390/membranes14110231
  9. J Am Chem Soc. 2024 Nov 29.
    Hydrogen-Deuterium Exchange Mass Spectrometry Reveals Mechanistic Insights into RNA Oligonucleotide-Mediated Inhibition of TDP-43 Aggregation.
    Thomas C Minshull, Emily J Byrd, Monika Olejnik, Antonio N Calabrese.
      Deposits of aggregated TAR DNA-binding protein 43 (TDP-43) in the brain are associated with several neurodegenerative diseases. It is well established that binding of RNA/DNA to TDP-43 can prevent TDP-43 aggregation, but an understanding of the structure(s) and conformational dynamics of TDP-43, and TDP-43-RNA complexes, is lacking, including knowledge of how the solution environment modulates these properties. Here, we address this challenge using hydrogen-deuterium exchange-mass spectrometry. In the presence of RNA olignoucleotides, we observe protection from exchange in the RNA recognition motif (RRM) domains of TDP-43 and the linker region between the RRM domains, consistent with nucleic acid binding modulating interdomain interactions. Intriguingly, at elevated salt concentrations, the extent of protection from exchange is reduced in the RRM domains when bound to an RNA sequence derived from the 3' UTR of the TDP-43 mRNA (CLIP34NT) compared to when bound to a (UG)6 repeat sequence. Under these conditions, CLIP34NT is no longer able to prevent TDP-43 aggregation. This suggests that a salt-induced structural rearrangement occurs when bound to this RNA, which may play a role in facilitating aggregation. Additionally, upon RNA binding, we identify differences in exchange within the short α-helical region located in the C-terminal domain (CTD) of TDP-43. These allosterically altered regions may influence the ability of TDP-43 to aggregate and fine-tune its RNA binding repertoire. Combined, these data provide additional insights into the intricate interplay between TDP-43 aggregation and RNA binding, an understanding of which is crucial for unraveling the molecular mechanisms underlying TDP-43-associated neurodegeneration.
    DOI:  https://doi.org/10.1021/jacs.4c11229
  10. Mol Cells. 2024 Nov 25. pii: S1016-8478(24)00186-9. [Epub ahead of print] 100161
    Young rat microbiota extracts strongly inhibit fibrillation of α-synuclein and protect neuroblastoma cells and zebrafish against α-synuclein toxicity.
    Mohaddeseh Ghorbani Shiraz, Janni Nielsen, Jeremias Widmann, Ka Hang Karen Chung, Thomas Paul Davis, Casper Rasmussen, Carsten Scavenius, Jan J Enghild, Camille Martin-Gallausiaux, Yogesh Singh, Ibrahim Javed, Daniel E Otzen.
      The clinical manifestations of Parkinson's Disease (PD) are driven by aggregation of α-Synuclein (α-Syn) in the brain. However, there is increasing evidence that PD may be initiated in the gut and thence spread to the brain, e.g. via the vagus nerve. Many studies link PD to changes in the gut microbiome, and bacterial amyloid has been shown to stimulate α-syn aggregation. Yet we are not aware of any studies reporting on a direct connection between microbiome components and α-Syn aggregation. Here we report that soluble extract from the gut microbiome of the rats, particularly young rats transgenic for PD, show a remarkably strong ability to inhibit in vitro α-Syn aggregation and keep it natively unfolded and monomeric. The active component(s) are heat-labile molecule(s) of around 30-100 kDa size which are neither nucleic acid nor lipid. Proteomic analysis identified several proteins whose concentrations in different rat samples correlated with the samples' anti-inhibitory activity, while a subsequent pulldown assay linked the protein chaperone DnaK with the inhibitory activity of young rat's microbiome, confirmed in subsequent in vitro assays. Remarkably, the microbiome extracts also protected neuroblastoma SH-SY5Y cells and zebrafish embryos against α-Syn toxicity. Our study sheds new light on the gut microbiome as a potential source of protection against PD and opens up for new microbiome-based therapeutic strategies.
    Keywords:  Parkinson’s Disease; aggregation; microbiome; proteomics; seeding
    DOI:  https://doi.org/10.1016/j.mocell.2024.100161
  11. Res Sq. 2024 Nov 19. pii: rs.3.rs-5306005. [Epub ahead of print]
    Divergent and Convergent TMEM106B Pathology in Murine Models of Neurodegeneration and Human Disease.
    Muzi Du, Suleyman C Akerman, Charlotte M Fare, Linhao Ruan, Svetlana Vidensky, Lyudmila Mamedova, Joshua Lee, Jeffrey D Rothstein.
      TMEM106B is a lysosomal/late endosome protein that is a potent genetic modifier of multiple neurodegenerative diseases as well as general aging. Recently, TMEM106B was shown to form insoluble aggregates in postmortem human brain tissue, drawing attention to TMEM106B pathology and the potential role of TMEM106B aggregation in disease. In the context of neurodegenerative diseases, TMEM106B has been studied in vivo using animal models of neurodegeneration, but these studies rely on overexpression or knockdown approaches. To date, endogenous TMEM106B pathology and its relationship to known canonical pathology in animal models has not been reported. Here, we analyze histological patterns of TMEM106B in murine models of C9ORF72 -related amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD), SOD1-related ALS, and tauopathy and compare these to postmortem human tissue from patients with C9-ALS/FTD, Alzheimer's disease (AD), and AD with limbic-predominant age-related TDP-43 encephalopathy (AD/LATE). We show that there are significant differences between TMEM106B pathology in mouse models and human patient tissue. Importantly, we also identified convergent evidence from both murine models and human patients that links TMEM106B pathology to TDP-43 nuclear clearance specifically in C9-ALS. Similarly, we find a relationship at the cellular level between TMEM106B pathology and phosphorylated Tau burden in Alzheimer's disease. By characterizing endogenous TMEM106B pathology in both mice and human postmortem tissue, our work reveals considerations that must be taken into account when analyzing data from in vivo mouse studies and elucidates new insights supporting the involvement of TMEM106B in the pathogenesis and progression of multiple neurodegenerative diseases.
    DOI:  https://doi.org/10.21203/rs.3.rs-5306005/v1
  12. Mol Neurodegener. 2024 Nov 29. 19(1): 92
    Seeding activity of skin misfolded tau as a biomarker for tauopathies.
    Zerui Wang, Ling Wu, Maria Gerasimenko, Tricia Gilliland, Zahid Syed Ali Shah, Evalynn Lomax, Yirong Yang, Steven A Gunzler, Vincenzo Donadio, Rocco Liguori, Bin Xu, Wen-Quan Zou.
       BACKGROUND: Tauopathies are a group of age-related neurodegenerative diseases characterized by the accumulation of pathologically hyperphosphorylated tau protein in the brain, leading to prion-like aggregation and propagation. They include Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick's disease (PiD). Currently, reliable diagnostic biomarkers that directly reflect the capability of propagation and spreading of misfolded tau aggregates in peripheral tissues and body fluids are lacking.
    METHODS: We utilized the seed-amplification assay (SAA) employing ultrasensitive real-time quaking-induced conversion (RT-QuIC) to assess the prion-like seeding activity of pathological tau in the skin of cadavers with neuropathologically confirmed tauopathies, including AD, PSP, CBD, and PiD, compared to normal controls.
    RESULTS: We found that the skin tau-SAA demonstrated a significantly higher sensitivity (75-80%) and specificity (95-100%) for detecting tauopathy, depending on the tau substrates used. Moreover, the increased tau-seeding activity was also observed in biopsy skin samples from living AD and PSP patients examined. Analysis of the end products of skin-tau SAA confirmed that the increased seeding activity was accompanied by the formation of tau aggregates with different physicochemical properties related to two different tau substrates used.
    CONCLUSIONS: Overall, our study provides proof-of-concept that the skin tau-SAA can differentiate tauopathies from normal controls, suggesting that the seeding activity of misfolded tau in the skin could serve as a diagnostic biomarker for tauopathies.
    Keywords:  Alzheimer’s disease; Real-time quaking-induced conversion (RT-QuIC); Seeding activity; Skin; Tau; Tauopathies
    DOI:  https://doi.org/10.1186/s13024-024-00781-1
  13. Int J Mol Sci. 2024 Nov 14. pii: 12220. [Epub ahead of print]25(22):
    Erucin, a Natural Isothiocyanate, Prevents Polyglutamine-Induced Toxicity in Caenorhabditis elegans via aak-2/AMPK and daf-16/FOXO Signaling.
    Martina Balducci, Julia Tortajada Pérez, Cristina Trujillo Del Río, Mar Collado Pérez, Andrea Del Valle Carranza, Ana Pilar Gomez Escribano, Rafael P Vázquez-Manrique, Andrea Tarozzi.
      Several neurodegenerative diseases (NDDs), such as Huntington's disease, six of the spinocerebellar ataxias, dentatorubral-pallidoluysian atrophy, and spinobulbar muscular atrophy, are caused by abnormally long polyglutamine (polyQ) tracts. Natural compounds capable of alleviating polyQ-induced toxicity are currently of great interest. In this work, we investigated the modulatory effect against polyQ neurotoxic aggregates exerted by erucin (ERN), an isothiocyanate naturally present in its precursor glucoerucin in rocket salad leaves and in its oxidized form, sulforaphane (SFN), in broccoli. Using C. elegans models expressing polyQ in different tissues, we demonstrated that ERN protects against polyQ-induced toxicity and that its action depends on the catalytic subunit of AMP-activated protein kinase (aak-2/AMPKα2) and, downstream in this pathway, on the daf-16/FOXO transcription factor, since nematodes deficient in aak-2/AMPKα2 and daf-16 did not respond to the treatment, respectively. Although triggered by a different source of neurotoxicity than polyQ diseases, i.e., by α-synuclein (α-syn) aggregates, Parkinson's disease (PD) was also considered in our study. Our results showed that ERN reduces α-syn aggregates and slightly improves the motility of worms. Therefore, further preclinical studies in mouse models of protein aggregation are justified and could provide insights into testing whether ERN could be a potential neuroprotective compound in humans.
    Keywords:  AMPK; Caenorhabditis elegans; daf-16/FOXO; erucin; neuroprotection; polyQ toxicity
    DOI:  https://doi.org/10.3390/ijms252212220
  14. Chem Sci. 2024 Nov 12.
    Discovery of penicillic acid as a chemical probe against tau aggregation in Alzheimer's disease.
    Jennifer Shyong, Jinliang Wang, Quoc-Dung Tran Huynh, Marina Fayzullina, Bo Yuan, Ching-Kuo Lee, Thomas Minehan, Paul M Seidler, Clay C C Wang.
      Alzheimer's Disease (AD) is a neurodegenerative disorder proven to be caused by the aggregation of protein tau into fibrils, resulting in neuronal death. The irreparable neuronal damage leads to irreversible symptoms with no cure; therefore, disaggregation of these tau fibrils could be targeted as a therapeutic approach to AD. Here we have developed a fungal natural product library to screen for secondary metabolites that have bioactive potential towards AD tau. Our initial screenings indicate that penicillic acid demonstrates anti-aggregation activity towards tau, while further in vitro experiments reveal that penicillic acid directly inhibits tau by disaggregating fibrils. Although penicillic acid possesses blood-brain barrier penetrability properties that are computationally predicted to be favorable, it is presumed to contain some mutagenic effects as well. To address this, we used the backbone of penicillic acid as a chemical probe to discover similar compounds that can inhibit AD tau aggregation with limited mutagenicity. This work suggests the potential of discovering chemical probes through natural product screening for small-molecule drug discovery of tauopathies.
    DOI:  https://doi.org/10.1039/d4sc05469e
  15. ACS Chem Neurosci. 2024 Nov 29.
    Detecting and Tracking β-Amyloid Oligomeric Forms and Dynamics In Vitro by a High-Sensitivity Fluorescent-Based Assay.
    Yanyan Zhao, Oleksandr Brener, Ewa Andrzejewska, Jiapeng Wei, CloudOuterMan Reiß, Ole Tietz, Tuomas P J Knowles, Franklin I Aigbirhio.
      Aggregation of β-amyloid protein is a hallmark pathology of the neurodegenerative disorder Alzheimer's disease and proceeds from monomers to insoluble misfolded fibril forms via soluble and highly toxic oligomeric intermediates. Given the dual feature of being the most toxic form of the Aβ aggregate proteome and an early marker of pathogenesis, there is a need for sensitive methods that can be used to detect Aβ oligomers and investigate the dynamics of aggregation. Herein, we describe a method based on the application of an oligomer-sensitive fluorescent chemical probe pTP-TFE combined with the use of a QIAD (Quantitative determination of Interference with Aβ Aggregate Size Distribution) assay to correctly identify Aβ oligomers in high sensitivity. pTP-TFE was evaluated and compared to thioflavin T and pFTAA, the two most widely used amyloid fibril dyes, and shown to be the only probe capable of detecting significant differences across all oligomeric species of β-amyloid. Furthermore, by observing changes in pTP-TFE fluorescence emission over time, we could track the dynamics of oligomer populations and thereby obtain kinetic information on the Aβ42 dynamic aggregation model. Therefore, we have established a highly sensitive, readily available, and simple method for studying β-amyloid protein aggregation dynamics.
    Keywords:  Alzheimer’s disease; amyloid oligomers; fluorescent probes; medicinal chemistry; neurological agents; oligomer dissociation kinetics
    DOI:  https://doi.org/10.1021/acschemneuro.4c00312
  16. Sci Transl Med. 2024 Nov 27. 16(775): eadp5730
    Seeding-competent TDP-43 persists in human patient and mouse muscle.
    Eileen M Lynch, Sara Pittman, Jil Daw, Chiseko Ikenaga, Sheng Chen, Dhruva D Dhavale, Meredith E Jackrel, Yuna M Ayala, Paul Kotzbauer, Cindy V Ly, Alan Pestronk, Thomas E Lloyd, Conrad C Weihl.
      TAR DNA binding protein 43 (TDP-43) is an RNA binding protein that accumulates as aggregates in the central nervous systems of some patients with neurodegenerative diseases. However, TDP-43 aggregation is also a sensitive and specific pathologic feature found in a family of degenerative muscle diseases termed inclusion body myopathy. TDP-43 aggregates from amyotrophic lateral sclerosis (ALS) and frontotemporal dementia brain lysates may serve as self-templating aggregate seeds in vitro and in vivo, supporting a prion-like spread from cell to cell. Whether a similar process occurs in patient muscle is not clear. We developed a mouse model of inducible, muscle-specific cytoplasmic localized TDP-43. These mice develop muscle weakness with robust accumulation of insoluble and phosphorylated sarcoplasmic TDP-43, leading to eosinophilic inclusions, altered proteostasis, and changes in TDP-43-related RNA processing that resolve with the removal of doxycycline. Skeletal muscle lysates from these mice also have seeding-competent TDP-43, as determined by a FRET-based biosensor, that persists for weeks upon resolution of TDP-43 aggregate pathology. Human muscle biopsies with TDP-43 pathology also contain TDP-43 aggregate seeds. Using lysates from muscle biopsies of patients with sporadic inclusion body myositis (IBM), immune-mediated necrotizing myopathy (IMNM), and ALS, we found that TDP-43 seeding capacity was specific to IBM. TDP-43 seeding capacity anticorrelated with TDP-43 aggregate and vacuole abundance. These data support that TDP-43 aggregate seeds are present in IBM skeletal muscle and represent a unique TDP-43 pathogenic species not previously appreciated in human muscle disease.
    DOI:  https://doi.org/10.1126/scitranslmed.adp5730
  17. Int J Mol Sci. 2024 Nov 10. pii: 12079. [Epub ahead of print]25(22):
    SARS-CoV-2 Infection and Alpha-Synucleinopathies: Potential Links and Underlying Mechanisms.
    Joanna Agata Motyl, Grażyna Gromadzka, Grzegorz Arkadiusz Czapski, Agata Adamczyk.
      Alpha-synuclein (α-syn) is a 140-amino-acid, intrinsically disordered, soluble protein that is abundantly present in the brain. It plays a crucial role in maintaining cellular structures and organelle functions, particularly in supporting synaptic plasticity and regulating neurotransmitter turnover. However, for reasons not yet fully understood, α-syn can lose its physiological role and begin to aggregate. This altered α-syn disrupts dopaminergic transmission and causes both presynaptic and postsynaptic dysfunction, ultimately leading to cell death. A group of neurodegenerative diseases known as α-synucleinopathies is characterized by the intracellular accumulation of α-syn deposits in specific neuronal and glial cells within certain brain regions. In addition to Parkinson's disease (PD), these conditions include dementia with Lewy bodies (DLBs), multiple system atrophy (MSA), pure autonomic failure (PAF), and REM sleep behavior disorder (RBD). Given that these disorders are associated with α-syn-related neuroinflammation-and considering that SARS-CoV-2 infection has been shown to affect the nervous system, with COVID-19 patients experiencing neurological symptoms-it has been proposed that COVID-19 may contribute to neurodegeneration in PD and other α-synucleinopathies by promoting α-syn misfolding and aggregation. In this review, we focus on whether SARS-CoV-2 could act as an environmental trigger that facilitates the onset or progression of α-synucleinopathies. Specifically, we present new evidence on the potential role of SARS-CoV-2 in modulating α-syn function and discuss the causal relationship between SARS-CoV-2 infection and the development of parkinsonism-like symptoms.
    Keywords:  COVID-19; Parkinson’s disease; SARS-CoV-2; alpha-synuclein; alpha-synucleinopathies; neurodegenerative diseases
    DOI:  https://doi.org/10.3390/ijms252212079
  18. Biochem Biophys Res Commun. 2024 Nov 23. pii: S0006-291X(24)01589-4. [Epub ahead of print]741 151053
    Liquid-liquid phase separation of tau and α-synuclein: A new pathway of overlapping neuropathologies.
    Leandro Cruz Rodríguez, Nahuel N Foressi, M Soledad Celej.
      Liquid-liquid phase separation (LLPS) is a critical phenomenon that leads to the formation of liquid-like membrane-less organelles within cells. Advances in our understanding of condensates reveal their significant roles in biology and highlight how their dysregulation may contribute to disease. Recent evidence indicates that the high protein concentration in coacervates may lead to abnormal protein aggregation associated with several neurodegenerative diseases. The presence of condensates containing multiple amyloidogenic proteins may play a role in the co-deposition and comorbidity seen in neurodegeneration. This review first provides a brief overview of the physicochemical bases and molecular determinants of LLPS. It then summarizes our understanding of Tau and α-synuclein (AS) phase separation, key proteins in Alzheimer's and Parkinson's diseases. By integrating recent findings on complex Tau and AS coacervation, this article offers a fresh perspective on how LLPS may contribute to the pathological overlap in neurodegenerative disorders and provide a novel therapeutic target to mitigate or prevent such conditions.
    Keywords:  Alzheimer; Amyloid; Condensates; Neurodegeneration; Parkinson; Phase separation
    DOI:  https://doi.org/10.1016/j.bbrc.2024.151053
This page is being maintained by Thomas Krichel. It was last updated on 2024‒12‒12 at 13:11.