bims-indpro Biomed News
on Intrinsically disordered proteins
Issue of 2022–05–08
fourteen papers selected by
Sara Mingu, Johannes Gutenberg University
  1. Predicting Protein Conformational Disorder and Disordered Binding Sites.
  2. Competing interactions give rise to two-state behavior and switch-like transitions in charge-rich intrinsically disordered proteins.
  3. Minimalist Design of an Intrinsically Disordered Protein-Mimicking Scaffold for an Artificial Membraneless Organelle.
  4. Prediction of the Effect of pH on the Aggregation and Conditional Folding of Intrinsically Disordered Proteins with SolupHred and DispHred.
  5. F/YGG-motif is an intrinsically disordered nucleic-acid binding motif.
  6. Study of Protein Dynamics via Neutron Spin Echo Spectroscopy.
  7. Kinetic coherence underlies the dynamics of disordered proteins.
  8. Vulnerability of HIF1α and HIF2α to damage by proteotoxic stressors.
  9. Cell cycle-specific phase separation regulated by protein charge blockiness.
  10. Structure-dependent recruitment and diffusion of guest proteins in liquid droplets of FUS.
  11. TDP-43 Oligomerization and Phase Separation Properties Are Necessary for Autoregulation.
  12. Comprehensive Folding Variations for Protein Folding.
  13. Evolution of α-synuclein conformation ensemble toward amyloid fibril via liquid-liquid phase separation (LLPS) as investigated by dynamic nuclear polarization-enhanced solid-state MAS NMR.
  14. Ultrastructural and biochemical classification of pathogenic tau, α-synuclein and TDP-43.
  1. Methods Mol Biol. 2022 ;2449 95-147
    Predicting Protein Conformational Disorder and Disordered Binding Sites.
    Ketty C Tamburrini, Giulia Pesce, Juliet Nilsson, Frank Gondelaud, Andrey V Kajava, Jean-Guy Berrin, Sonia Longhi.
      In the last two decades it has become increasingly evident that a large number of proteins adopt either a fully or a partially disordered conformation. Intrinsically disordered proteins are ubiquitous proteins that fulfill essential biological functions while lacking a stable 3D structure. Their conformational heterogeneity is encoded by the amino acid sequence, thereby allowing intrinsically disordered proteins or regions to be recognized based on their sequence properties. The identification of disordered regions facilitates the functional annotation of proteins and is instrumental for delineating boundaries of protein domains amenable to crystallization. This chapter focuses on the methods currently employed for predicting protein disorder and identifying intrinsically disordered binding sites.
    Keywords:  Disorder databases and metaservers; Induced folding; Intrinsic disorder; Intrinsically disordered binding sites; Intrinsically disordered proteins; Intrinsically disordered regions; MoREs; MoRFs; Prediction methods and tools
    DOI:  https://doi.org/10.1007/978-1-0716-2095-3_4
  2. Proc Natl Acad Sci U S A. 2022 May 10. 119(19): e2200559119
    Competing interactions give rise to two-state behavior and switch-like transitions in charge-rich intrinsically disordered proteins.
    Xiangze Zeng, Kiersten M Ruff, Rohit V Pappu.
      SignificanceIntrinsically disordered regions (IDRs) of proteins, when tethered to folded domains, function either as flexible tails or as linkers between domains. Most IDRs are polyampholytes that comprise a mixture of oppositely charged residues. Recent measurements of tethered polyampholytes showed the tendency of arginine- and lysine-rich sequences to behave very differently from one another. Using computer simulations, we show that these differences are determined by differences in free energies of hydration, steric volumes, and other considerations. Further, the interplay between electrostatic attractions and favorable free energies of hydration creates distinct stable states for polyampholytic IDRs. These findings have implications for switch-like transitions and the regulation of effective concentrations of interaction motifs by IDRs.
    Keywords:  bistable; intrinsically disordered proteins; polyampholyte; polyzwitterion
    DOI:  https://doi.org/10.1073/pnas.2200559119
  3. ACS Cent Sci. 2022 Apr 27. 8(4): 493-500
    Minimalist Design of an Intrinsically Disordered Protein-Mimicking Scaffold for an Artificial Membraneless Organelle.
    Jianhui Liu, Fariza Zhorabek, Xin Dai, Jinqing Huang, Ying Chau.
      Liquid-liquid phase separation (LLPS) is an emerging and universal mechanism for intracellular organization, particularly, by forming membraneless organelles (MLOs) hosting intrinsically disordered proteins (IDPs) as scaffolds. Genetic engineering is generally applied to reconstruct IDPs harboring over 100 amino acid residues. Here, we report the first design of synthetic hybrids consisting of short oligopeptides of fewer than 10 residues as "stickers" and dextran as a "spacer" to recapitulate the characteristics of IDPs, as exemplified by the multivalent FUS protein. Hybrids undergo LLPS into micron-sized liquid droplets resembling LLPS in vitro and in living cells. Moreover, the droplets formed are capable of recruiting proteins and RNAs and providing a favorable environment for a biochemical reaction with highly enriched components, thereby mimicking the function of natural MLOs. This simple yet versatile model system can help elucidate the molecular interactions implicated in MLOs and pave ways to a new type of biomimetic materials.
    DOI:  https://doi.org/10.1021/acscentsci.1c01021
  4. Methods Mol Biol. 2022 ;2449 197-211
    Prediction of the Effect of pH on the Aggregation and Conditional Folding of Intrinsically Disordered Proteins with SolupHred and DispHred.
    Valentín Iglesias, Carlos Pintado-Grima, Jaime Santos, Marc Fornt, Salvador Ventura.
      Proteins microenvironments modulate their structures. Binding partners, organic molecules, or dissolved ions can alter the protein's compaction, inducing aggregation or order-disorder conformational transitions. Surprisingly, bioinformatic platforms often disregard the protein context in their modeling. In a recent work, we proposed that modeling how pH affects protein net charge and hydrophobicity might allow us to forecast pH-dependent aggregation and conditional disorder in intrinsically disordered proteins (IDPs). As these approaches showed remarkable success in recapitulating the available bibliographical data, we made these prediction methods available for the scientific community as two user-friendly web servers. SolupHred is the first dedicated software to predict pH-dependent aggregation, and DispHred is the first pH-dependent predictor of protein disorder. Here we dissect the features of these two software applications to train and assist scientists in studying pH-dependent conformational changes in IDPs.
    Keywords:  Aggregation prediction; Amyloid; Bioinformatics; Conditional folding; Disorder prediction; IDPs; Machine learning; Protein aggregation; Protein compaction; pH
    DOI:  https://doi.org/10.1007/978-1-0716-2095-3_8
  5. RNA Biol. 2022 Jan;19(1): 622-635
    F/YGG-motif is an intrinsically disordered nucleic-acid binding motif.
    Joris Van Lindt, Tamas Lazar, Donya Pakravan, Manon Demulder, Attila Meszaros, Ludo Van Den Bosch, Dominique Maes, Peter Tompa.
      Heterogeneous nuclear ribonucleoproteins (hnRNP) function in RNA processing, have RNA-recognition motifs (RRMs) and intrinsically disordered, low-complexity domains (LCDs). While RRMs are drivers of RNA binding, there is only limited knowledge about the RNA interaction by the LCD of some hnRNPs. Here, we show that the LCD of hnRNPA2 interacts with RNA via an embedded Tyr/Gly-rich region which is a disordered RNA-binding motif. RNA binding is maintained upon mutating tyrosine residues to phenylalanines, but abrogated by mutating to alanines, thus we term the RNA-binding region 'F/YGG motif'. The F/YGG motif can bind a broad range of structured (e.g. tRNA) and disordered (e.g. polyA) RNAs, but not rRNA. As the F/YGG otif can also interact with DNA, we consider it a general nucleic acid-binding motif. hnRNPA2 LCD can form dense droplets, by liquid-liquid phase separation (LLPS). Their formation is inhibited by RNA binding, which is mitigated by salt and 1,6-hexanediol, suggesting that both electrostatic and hydrophobic interactions feature in the F/YGG motif. The D290V mutant also binds RNA, which interferes with both LLPS and aggregation thereof. We found homologous regions in a broad range of RNA- and DNA-binding proteins in the human proteome, suggesting that the F/YGG motif is a general nucleic acid-interaction motif.
    Keywords:  Liquid-liquid phase separation; disordered proteins; low complexity domain; nucleic acid interaction; sequence motif
    DOI:  https://doi.org/10.1080/15476286.2022.2066336
  6. J Vis Exp. 2022 Apr 13.
    Study of Protein Dynamics via Neutron Spin Echo Spectroscopy.
    Laura-Roxana Stingaciu.
      Most human body proteins' activity and functionality are related to configurational changes of entire subdomains within the protein crystal structure. The crystal structures build the basis for any calculation that describes the structure or dynamics of a protein, most of the time with strong geometrical restrictions. However, these restrictions from the crystal structure are not present in the solution. The structure of the proteins in the solution may differ from the crystal due to rearrangements of loops or subdomains on the pico to nanosecond time scale (i.e., the internal protein dynamics time regime). The present work describes how slow motions on timescales of several tens of nanoseconds can be accessed using neutron scattering. In particular, the dynamical characterization of two major human proteins, an intrinsically disordered protein that lacks a well-defined secondary structure and a classical antibody protein, is addressed by neutron spin echo spectroscopy (NSE) combined with a wide range of laboratory characterization methods. Further insights into protein domain dynamics were achieved using mathematical modeling to describe the experimental neutron data and determine the crossover between combined diffusive and internal protein motions. The extraction of the internal dynamic contribution to the intermediate scattering function obtained from NSE, including the timescale of the various movements, allows further vision into the mechanical properties of single proteins and the softness of proteins in their nearly natural environment in the crowded protein solution.
    DOI:  https://doi.org/10.3791/61862
  7. RSC Adv. 2021 Nov 04. 11(57): 36242-36249
    Kinetic coherence underlies the dynamics of disordered proteins.
    Alexander Tenenbaum.
      The dynamics of two proteins of similar size, the globular lysozyme and the intrinsically disordered Huntingtin interacting protein, has been simulated in three states resembling a globule, a pre-molten globule, and a molten globule. A coherence time τ has been defined, measuring the delay in the display of a stochastic behaviour after a perturbation of the system. This time has been computed for two sets of collective variables: the projection of the phase point onto the positions and momenta subspaces (τ r and τ p ), and the principal components (PCs) of positions q and momenta π produced by a covariance analysis in these subspaces (τ q and τ π ). In all states τ p ≈ 3.5τ r , and τ π ≈ 3.5τ q . The coherence times of individual PCs, τ (l) q and τ (l) π, have also been computed, and τ (l) π > τ (l) q in all states. The prevalence of τ p over τ r , or of τ π over τ q , drives the dynamics of the protein over a time range of ≈1-2 ps; moreover, a hidden synchronism appears to raise the momenta subspace's coherence above that of its individual PCs. In the transition of lysozyme to the molten globule the τ (l) q decrease but, unexpectedly, the τ (l) π increase; after this transition τ p ≈ 5τ r and τ π ≈ 5τ q . A gain of kinetic coherence accompanies thus the loss of structural coherence caused by the denaturation of the protein in the transition from globule to molten globule. The increase of the τ (l) π does not take place in the analogous transition of the Huntingtin protein. These results are compared with those of a similar analysis performed on three pseudo-proteins designed by scrambling the primary sequence of the Huntingtin interacting protein, and on two oligopeptides. The hidden synchronism appears to be a generic property of these polypeptides. The τ (l) π spectrum is similar in denaturated and in intrinsically disordered biomolecules; but the gain of kinetic coherence as a result of denaturation seems to be a specific property of the biologically functional lysozyme.
    DOI:  https://doi.org/10.1039/d1ra06823g
  8. Toxicol Appl Pharmacol. 2022 Apr 30. pii: S0041-008X(22)00186-7. [Epub ahead of print]445 116041
    Vulnerability of HIF1α and HIF2α to damage by proteotoxic stressors.
    Lauren M Meyers, Casey Krawic, Michal W Luczak, Anatoly Zhitkovich.
      Transcription factors HIF1 and HIF2 are central regulators of physiological responses to hypoxia and important for normal functioning of tissue stem cells and maintenance of healthy microvasculature. Even modest decreases in HIF activity exert detrimental effects in tissues although it is unclear what factors can directly impair HIF functions. We hypothesized that the presence of functionally important, large intrinsically disordered regions in HIFα subunits of HIF1/2 could make them structurally vulnerable to protein-damaging conditions. We found that common protein-damaging agents such as endogenous/exogenous aldehydes (formaldehyde, acetaldehyde), moderate heat shock and the environmental toxicant cadmium cause inactivation of HIF1 and HIF2 due to structural damage to HIFα subunits. Aldehydes triggered a rapid and selective depletion of HIF1α and HIF2α, which occurred as a result of enhanced binding of Pro-hydroxylated/VHL-ubiquitinated HIFα by 26S proteasomes. In the absence of proteasomal degradation, aldehyde-damaged HIF1 and HIF2 were transactivation defective and HIFα subunits became insoluble/denatured when their VHL-mediated ubiquitination was blocked. Protein damage by heat shock and cadmium resulted in the insolubility of Pro-nonhydroxylated HIFα. Thus, VHL-dependent ubiquitination of damaged HIFα also acts as means to maintain their solubility, permitting capture by proteasomes. The observed control of HIFα stability at the point of proteasome binding may extend to several posttranslational modifications that occur in the conformationally flexible regions of these proteins. Our findings revealed vulnerability of HIF1 and HIF2 to direct inactivation by protein-damaging agents, which helps understand their tissue injury mechanisms and favorable responses of hypoxic tumors to hyperthermia.
    Keywords:  Cadmium; Formaldehyde; HIF1A; HIF2A; Heat shock; Proteotoxicity
    DOI:  https://doi.org/10.1016/j.taap.2022.116041
  9. Nat Cell Biol. 2022 May 05.
    Cell cycle-specific phase separation regulated by protein charge blockiness.
    Hiroya Yamazaki, Masatoshi Takagi, Hidetaka Kosako, Tatsuya Hirano, Shige H Yoshimura.
      Dynamic morphological changes of intracellular organelles are often regulated by protein phosphorylation or dephosphorylation1-6. Phosphorylation modulates stereospecific interactions among structured proteins, but how it controls molecular interactions among unstructured proteins and regulates their macroscopic behaviours remains unknown. Here we determined the cell cycle-specific behaviour of Ki-67, which localizes to the nucleoli during interphase and relocates to the chromosome periphery during mitosis. Mitotic hyperphosphorylation of disordered repeat domains of Ki-67 generates alternating charge blocks in these domains and increases their propensity for liquid-liquid phase separation (LLPS). A phosphomimetic sequence and the sequences with enhanced charge blockiness underwent strong LLPS in vitro and induced chromosome periphery formation in vivo. Conversely, mitotic hyperphosphorylation of NPM1 diminished a charge block and suppressed LLPS, resulting in nucleolar dissolution. Cell cycle-specific phase separation can be modulated via phosphorylation by enhancing or reducing the charge blockiness of disordered regions, rather than by attaching phosphate groups to specific sites.
    DOI:  https://doi.org/10.1038/s41556-022-00903-1
  10. Sci Rep. 2022 May 02. 12(1): 7101
    Structure-dependent recruitment and diffusion of guest proteins in liquid droplets of FUS.
    Kiyoto Kamagata, Nanako Iwaki, Saori Kanbayashi, Trishit Banerjee, Rika Chiba, Virginie Gaudon, Bertrand Castaing, Seiji Sakomoto.
      Liquid droplets of a host protein, formed by liquid-liquid phase separation, recruit guest proteins and provide functional fields. Recruitment into p53 droplets is similar between disordered and folded guest proteins, whereas the diffusion of guest proteins inside droplets depends on their structural types. In this study, to elucidate how the recruitment and diffusion properties of guest proteins are affected by a host protein, we characterized the properties of guest proteins in fused in sarcoma (FUS) droplets using single-molecule fluorescence microscopy in comparison with p53 droplets. Unlike p53 droplets, disordered guest proteins were recruited into FUS droplets more efficiently than folded guest proteins, suggesting physical exclusion of the folded proteins from the small voids of the droplet. The recruitment did not appear to depend on the physical parameters (electrostatic or cation-π) of guests, implying that molecular size exclusion limits intermolecular interaction-assisted uptake. The diffusion of disordered guest proteins was comparable to that of the host FUS, whereas that of folded proteins varied widely, similar to the results for host p53. The scaling exponent of diffusion highlights the molecular sieving of large folded proteins in droplets. Finally, we proposed a molecular recruitment and diffusion model for guest proteins in FUS droplets.
    DOI:  https://doi.org/10.1038/s41598-022-11177-w
  11. Front Neurosci. 2022 ;16 818655
    TDP-43 Oligomerization and Phase Separation Properties Are Necessary for Autoregulation.
    Lydia C Koehler, Zachary R Grese, Alliny C S Bastos, Lohany D Mamede, Tomasz Heyduk, Yuna M Ayala.
      Loss of TDP-43 protein homeostasis and dysfunction, in particular TDP-43 aggregation, are tied to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 is an RNA binding protein tightly controlling its own expression levels through a negative feedback loop, involving TDP-43 recruitment to the 3' untranslated region of its own transcript. Aberrant TDP-43 expression caused by autoregulation defects are linked to TDP-43 pathology. Therefore, interactions between TDP-43 and its own transcript are crucial to prevent TDP-43 aggregation and loss of function. However, the mechanisms that mediate this interaction remain ill-defined. We find that a central RNA sequence in the 3' UTR, which mediates TDP-43 autoregulation, increases the liquid properties of TDP-43 phase separation. Furthermore, binding to this RNA sequence induces TDP-43 condensation in human cell lysates, suggesting that this interaction promotes TDP-43 self-assembly into dynamic ribonucleoprotein granules. In agreement with these findings, our experiments show that TDP-43 oligomerization and phase separation, mediated by the amino and carboxy-terminal domains, respectively, are essential for TDP-43 autoregulation. According to our additional observations, CLIP34-associated phase separation and autoregulation may be efficiently controlled by phosphorylation of the N-terminal domain. Importantly, we find that specific ALS-associated TDP-43 mutations, mainly M337V, and a shortened TDP-43 isoform recently tied to motor neuron toxicity in ALS, disrupt the liquid properties of TDP-43-RNA condensates as well as autoregulatory function. In addition, we find that M337V decreases the cellular clearance of TDP-43 and other RNA binding proteins associated with ALS/FTD. These observations suggest that loss of liquid properties in M337V condensates strongly affects protein homeostasis. Together, this work provides evidence for the central role of TDP-43 oligomerization and liquid-liquid phase separation linked to RNA binding in autoregulation. These mechanisms may be impaired by TDP-43 disease variants and controlled by specific cellular signaling.
    Keywords:  ALS; ALS mutations; RNA binding protein; TDP-43 (TAR DNA-binding protein 43); TDP-43 autoregulation; frontotemporal dementia (FTD); liquid-liquid phase separation (LLPS); protein aggregation
    DOI:  https://doi.org/10.3389/fnins.2022.818655
  12. Proteins. 2022 May 05.
    Comprehensive Folding Variations for Protein Folding.
    Jiaan Yang, Wen Xiang Cheng, Xiao Fei Zhao, Gang Wu, Shi Tong Sheng, Qiyue Hu, Hu Ge, Qianshan Qin, Xinshen Jin, Lianshan Zhang, Peng Zhang.
      The revelation of protein folding is a challenging subject in both discovery and description. Except for acquirement of accurate 3D structure in protein stable state, another big hurdle is how to discover structural flexibility for protein innate character. Even if a huge number of flexible conformations are known, difficulty is how to represent these conformations. A novel approach, protein structure fingerprint, has been developed to expose the comprehensive local folding variations, and then construct folding conformations for entire protein. The backbone of 5 amino acid residues was identified as a universal folden, and then a set of Protein Folding Shape Code (PFSC) was derived for completely covering folding space in alphabetic description. Sequentially, a database was created to collect all possible folding shapes of local folding variations for all permutation of 5 amino acids. Successively, Protein Folding Variation Matrix (PFVM) assembled all possible local folding variations along sequence for a protein, which possesses several prominent features. First, it showed the fluctuation with certain folding patterns along sequence which revealed how the protein folding was related the order of amino acids in sequence. Second, all folding variations for an entire protein can be simultaneously apprehended at a glance within PFVM. Third, all conformations can be determined by local folding variations from PFVM, so total number of conformations is no longer ambiguous for any protein. Finally, the most possible folding conformation and its 3D structure can be acquired according PFVM for protein structure prediction. Therefore, the protein structure fingerprint approach provides a significant means for investigation of protein folding problem.
    Keywords:  alphabetic description; folding conformation; intrinsically disordered protein; protein conformation; protein folding; protein structure prediction
    DOI:  https://doi.org/10.1002/prot.26381
  13. Neurochem Int. 2022 Apr 29. pii: S0197-0186(22)00070-5. [Epub ahead of print] 105345
    Evolution of α-synuclein conformation ensemble toward amyloid fibril via liquid-liquid phase separation (LLPS) as investigated by dynamic nuclear polarization-enhanced solid-state MAS NMR.
    Mika Takamuku, Tomoaki Sugishita, Hajime Tamaki, Lingyingzi Dong, Masatomo So, Toshimichi Fujiwara, Yoh Matsuki.
      Protein fibrillation and human neurodegenerative diseases, with a profound underlying connection suggested between them, have been the subject of intense investigations in the medical, biophysical and bio-engineering sciences. For gaining the molecular mechanistic insights into such connection, i.e., the cause and effect, atomic-resolution molecular structure information especially on the initial oligomeric states is of paramount importance, not only that on the mature amyloid fibrils. α-Synuclein (αSyn) and its amyloid fibril has a direct relevance to the Parkinson's disease and other synucleinopathies, but what triggers the fibrillation is still not entirely clear. We here describe the liquid-liquid phase separation (LLPS) of αSyn and investigate its conformational evolution from its monomeric state into oligomer state within the early-stage of the phase-separated droplets, mainly using solution and magic-angle spinning (MAS) solid-state nuclear magnetic resonance (NMR) spectroscopies, aided with optical and fluorescent microscopies and CD spectroscopy. Based on the analysis of the intricately broadened shapes of the MAS NMR peaks observed for isotopically 13C-labeled His-50 of αSyn, we show that the distribution of the αSyn conformation is skewed from the initial completely random state to a loose β-rich ensembles at/around His-50 as early as day-3 (d3) within the droplet. This intra-droplet loose β-rich assembly showed a very slow progression until d8, and eventually maturated into ThT-positive, long and unbranched amyloid fibrils after 8 weeks. The obtained information on the evolution of the distribution of the conformation ensemble is unique, and difficult to obtain with X-ray crystallography and cryo-electron microscopy (cryoEM). In particular, the sensitivity-enhanced MAS NMR based on the low-temperature dynamic nuclear polarization (DNP) technique was proven to be a key tool in characterizing the conformational ensemble with dilute protein samples such as the liquid-phase droplets.
    Keywords:  Dynamic nuclear polarization (DNP)-Enhanced MAS NMR; Liquid-liquid phase separation (LLPS); Synuclein
    DOI:  https://doi.org/10.1016/j.neuint.2022.105345
  14. Acta Neuropathol. 2022 May 05.
    Ultrastructural and biochemical classification of pathogenic tau, α-synuclein and TDP-43.
    Airi Tarutani, Tadashi Adachi, Hiroyasu Akatsu, Yoshio Hashizume, Kazuko Hasegawa, Yuko Saito, Andrew C Robinson, David M A Mann, Mari Yoshida, Shigeo Murayama, Masato Hasegawa.
      Intracellular accumulation of abnormal proteins with conformational changes is the defining neuropathological feature of neurodegenerative diseases. The pathogenic proteins that accumulate in patients' brains adopt an amyloid-like fibrous structure and exhibit various ultrastructural features. The biochemical analysis of pathogenic proteins in sarkosyl-insoluble fractions extracted from patients' brains also shows disease-specific features. Intriguingly, these ultrastructural and biochemical features are common within the same disease group. These differences among the pathogenic proteins extracted from patients' brains have important implications for definitive diagnosis of the disease, and also suggest the existence of pathogenic protein strains that contribute to the heterogeneity of pathogenesis in neurodegenerative diseases. Recent experimental evidence has shown that prion-like propagation of these pathogenic proteins from host cells to recipient cells underlies the onset and progression of neurodegenerative diseases. The reproduction of the pathological features that characterize each disease in cellular and animal models of prion-like propagation also implies that the structural differences in the pathogenic proteins are inherited in a prion-like manner. In this review, we summarize the ultrastructural and biochemical features of pathogenic proteins extracted from the brains of patients with neurodegenerative diseases that accumulate abnormal forms of tau, α-synuclein, and TDP-43, and we discuss how these disease-specific properties are maintained in the brain, based on recent experimental insights.
    Keywords:  Prion-like propagation; Strains; Synucleinopathy; TDP-43; TDP-43 proteinopathy; Tau; Tauopathy; α-Synuclein
    DOI:  https://doi.org/10.1007/s00401-022-02426-3
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