bims-proned 2024-09-08 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2024‒09‒08
nineteen papers selected by
Verena Kohler, Umeå University

Misfolding and aggregation in neurodegenerative diseases: protein quality control machinery as potential therapeutic clearance pathways.
Simulating the anti-aggregative effect of fasudil in early dimerisation process of α-synuclein.
Aquaporin-4 mis-localization slows glymphatic clearance of α-synuclein and promotes α-synuclein pathology and aggregate propagation.
Understanding alpha-synuclein aggregation propensity in animals and humans.
Unraveling the Structure and Dynamics of Ac-PHF6-NH2 Tau Segment Oligomers.
Aggregate-selective removal of pathological tau by clustering-activated degraders.
Regulation of proteostasis by sleep through autophagy in Drosophila models of Alzheimer's disease.
DNAJB6 is expressed in neurons and oligodendrocytes of the human brain.
Alzheimer's Disease Seeded Tau Forms Paired Helical Filaments Yet Lacks Seeding Potential.
Tilorone mitigates the propagation of α-synucleinopathy in a midbrain-like organoid model.
Molecular Visualization of Neuronal TDP43 Pathology In Situ.
α-Synuclein-mediated mitochondrial translocation of cofilin-1 leads to oxidative stress and cell apoptosis in PD.
Glycosylation in aging and neurodegenerative diseases.
Nanoscale Structural Characterization of Amyloid β 1-42 Oligomers and Fibrils Grown in the Presence of Fatty Acids.
A charged tail on anti-α-Synuclein antibodies does not enhance their affinity to α-Synuclein fibrils.
alpha-synuclein, autophagy-lysosomal pathway, and Lewy bodies: mutations, propagation, aggregation, and the formation of inclusions.
Novel C. elegans models of Lewy body disease reveal pathological protein interactions and widespread miRNA dysregulation.
Basic approach on the protective effects of hesperidin and naringin in Alzheimer's disease.
Phosphorylation at serine 214 correlates with tau seeding activity in an age-dependent manner in two mouse models for tauopathies and is required for tau transsynaptic propagation.

Cell Commun Signal. 2024 Aug 30. 22(1): 421

Misfolding and aggregation in neurodegenerative diseases: protein quality control machinery as potential therapeutic clearance pathways.

Oliwia Koszła, Przemysław Sołek.

  The primary challenge in today's world of neuroscience is the search for new therapeutic possibilities for neurodegenerative disease. Central to these disorders lies among other factors, the aberrant folding, aggregation, and accumulation of proteins, resulting in the formation of toxic entities that contribute to neuronal degeneration. This review concentrates on the key proteins such as β-amyloid (Aβ), tau, and α-synuclein, elucidating the intricate molecular events underlying their misfolding and aggregation. We critically evaluate the molecular mechanisms governing the elimination of misfolded proteins, shedding light on potential therapeutic strategies. We specifically examine pathways such as the endoplasmic reticulum (ER) and unfolded protein response (UPR), chaperones, chaperone-mediated autophagy (CMA), and the intersecting signaling of Keap1-Nrf2-ARE, along with autophagy connected through p62. Above all, we emphasize the significance of these pathways as protein quality control mechanisms, encompassing interventions targeting protein aggregation, regulation of post-translational modifications, and enhancement of molecular chaperones and clearance. Additionally, we focus on current therapeutic possibilities and new, multi-target approaches. In conclusion, this review systematically consolidates insights into emerging therapeutic strategies predicated on protein aggregates clearance.

Keywords:  Aggregates; Chaperones; Misfolded proteins; Neurodegenerative disease; Tau; α-synuclein; β-amyloid

DOI:  https://doi.org/10.1186/s12964-024-01791-8
Biophys Chem. 2024 Aug 30. pii: S0301-4622(24)00148-0. [Epub ahead of print]314 107319

Simulating the anti-aggregative effect of fasudil in early dimerisation process of α-synuclein.

Sneha Menon, Jagannath Mondal.

  The aggregation of the protein α-synuclein into amyloid deposits is associated with multiple neurological disorders, including Parkinson's disease. Soluble amyloid oligomers are reported to exhibit higher toxicity than insoluble amyloid fibrils, with dimers being the smallest toxic oligomer. Small molecule drugs, such as fasudil, have shown potential in targeting α-synuclein aggregation and reducing its toxicity. In this study, we use atomistic molecular dynamics simulations to demonstrate how fasudil affects the earliest stage of aggregation, namely dimerization. Our results show that the presence of fasudil reduces the propensity for intermolecular contact formation between protein chains. Consistent with previous reports, our analysis confirms that fasudil predominantly interacts with the negatively charged C-terminal region of α-synuclein. However, we also observe transient interactions with residues in the charged N-terminal and hydrophobic NAC regions. Our simulations indicate that while fasudil prominently interacts with the C-terminal region, it is the transient interactions with residues in the N-terminal and NAC regions that effectively block the formation of intermolecular contacts between protein chains and prevent early dimerization of this disordered protein.

Keywords:  Alpha-synuclein; Intrinsically disordered protein; Oligomerization; Small-molecule

DOI:  https://doi.org/10.1016/j.bpc.2024.107319
bioRxiv. 2024 Aug 19. pii: 2024.08.14.607971. [Epub ahead of print]

Aquaporin-4 mis-localization slows glymphatic clearance of α-synuclein and promotes α-synuclein pathology and aggregate propagation.

Molly Braun, Matthew J Simon, Jay Jang, Keith Sanderson, Justyna Swierz, Mathew Sevao, Alexandra B Pincus, Allison J Schaser, Jonathan E Elliott, Miranda M Lim, Vivek K Unni, Abigail G Schindler, C Dirk Keene, Caitlin S Latimer, Jeffrey Iliff.

The appearance of misfolded and aggregated proteins is a pathological hallmark of numerous neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. Sleep disruption is proposed to contribute to these pathological processes and is a common early feature among neurodegenerative disorders. Synucleinopathies are a subclass of neurodegenerative conditions defined by the presence of α-synuclein aggregates, which may not only enhance cell death, but also contribute to disease progression by seeding the formation of additional aggregates in neighboring cells. The mechanisms driving intercellular transmission of aggregates remains unclear. We propose that disruption of sleep-active glymphatic function, caused by loss of precise perivascular AQP4 localization, inhibits α-synuclein clearance and facilitates α-synuclein propagation and seeding. We examined human post-mortem frontal cortex and found that neocortical α-synuclein pathology was associated with AQP4 mis-localization throughout the gray matter. Using a transgenic mouse model lacking the adapter protein α-syntrophin, we observed that loss of perivascular AQP4 localization impairs the glymphatic clearance of α-synuclein from intersititial to cerebrospinal fluid. Using a mouse model of α-synuclein propogation, using pre-formed fibril injection, we observed that loss of perivascular AQP4 localization increased α-synuclein aggregates. Our results indicate α-synuclein clearance and propagation are mediated by glymphatic function and that AQP4 mis-localization observed in the presence of human synucleinopathy may contribute to the development and propagation of Lewy body pathology in conditions such as Lewy Body Dementia and Parkinson's disease.

DOI: https://doi.org/10.1101/2024.08.14.607971
Biochem Biophys Rep. 2024 Sep;39 101810

Understanding alpha-synuclein aggregation propensity in animals and humans.

Natalie G Horgan, Annie M McCarty, Ashley A Hetak, Hailey B Penticoff, Jessica S Fortin.

  Alpha-synuclein (α-syn) aggregation plays a critical role in the pathogenicity of Parkinson's Disease (PD). This study aims to evaluate the aggregation propensity of α-syn fragment peptides designed using the variability found in humans and animals. Thioflavin T (ThT) and transmission electron microscopy (TEM) were used to validate the formation of fibrils to identify important amino acid residues. Human α-syn fragments 51-75, 37-61, 62-86, 76-100, and 116-140 demonstrate a significantly higher tendency to aggregate compared to fragments 1-25, 26-50, and 91-115. All species analyzed of the α-syn 37-61 and 62-86 regions were shown to form fibrils on both ThT and TEM. The α-syn 37-61 and 62-86 fragment regions exhibited a high susceptibility to aggregation, with fibril formation observed in all species. The A53T mutation in several α-syn 37-61 fragments may enhance their propensity for aggregation, suggesting a correlation between this mutation and the capacity for fibril formation. Furthermore, the presence of the non-amyloid-β component (NAC) region, specifically in α-syn 62-86, was consistently observed in several fragments that displayed fibril formation, indicating a potential correlation between the NAC region and the process of fibril formation in α-syn. Finally, the combination of a high quantity of valine and a low quantity of acidic amino acids in these fragments may serve as indicators of α-syn fibril formation.

Keywords:  Aggregation; Alpha-synuclein; Fibril; Parkinson's disease; Thioflavin T (ThT); Transmission electron microscopy (TEM)

DOI:  https://doi.org/10.1016/j.bbrep.2024.101810
ACS Chem Neurosci. 2024 Aug 30.

Unraveling the Structure and Dynamics of Ac-PHF6-NH2 Tau Segment Oligomers.

Iuliia Stroganova, Zenon Toprakcioglu, Hannah Willenberg, Tuomas P J Knowles, Anouk M Rijs.

  The aggregation of the proteins tau and amyloid-β is a salient feature of Alzheimer's disease, the most common form of neurodegenerative disorders. Upon aggregation, proteins transition from their soluble, monomeric, and functional state into insoluble, fibrillar deposits through a complex process involving a variety of intermediate species of different morphologies, including monomers, toxic oligomers, and insoluble fibrils. To control and direct peptide aggregation, a complete characterization of all species present and an understanding of the molecular processes along the aggregation pathway are essential. However, this is extremely challenging due to the transient nature of oligomers and the complexity of the reaction networks. Therefore, we have employed a combined approach that allows us to probe the structure and kinetics of oligomeric species, following them over time as they form fibrillar structures. Targeting the tau protein peptide segment Ac-PHF6-NH2, which is crucial for the aggregation of the full protein, soft nano-electrospray ionization combined with ion mobility mass spectrometry has been employed to study the kinetics of heparin-induced intact oligomer formation. The oligomers are identified and characterized using high-resolution ion mobility mass spectrometry, demonstrating that the addition of heparin does not alter the structure of the oligomeric species. The kinetics of fibril formation is monitored through a Thioflavin T fluorescence assay. Global fitting of the kinetic data indicates that secondary nucleation plays a key role in the aggregation of the Ac-PHF6-NH2 tau segment, while the primary nucleation rate is greatly accelerated by heparin.

Keywords:  Alzheimer’s disease; amyloid oligomers; ion mobility mass spectrometry; kinetics; peptide aggregation; tau

DOI:  https://doi.org/10.1021/acschemneuro.4c00404
Science. 2024 Aug 30. 385(6712): 1009-1016

Aggregate-selective removal of pathological tau by clustering-activated degraders.

Jonathan Benn, Shi Cheng, Sophie Keeling, Annabel E Smith, Marina J Vaysburd, Dorothea Böken, Lauren V C Miller, Taxiarchis Katsinelos, Catarina Franco, Elian Dupré, Clément Danis, Isabelle Landrieu, Luc Buée, David Klenerman, Leo C James, William A McEwan.

Selective degradation of pathological protein aggregates while sparing monomeric forms is of major therapeutic interest. The E3 ligase tripartite motif-containing protein 21 (TRIM21) degrades antibody-bound proteins in an assembly state-specific manner due to the requirement of TRIM21 RING domain clustering for activation, yet effective targeting of intracellular assemblies remains challenging. Here, we fused the RING domain of TRIM21 to a target-specific nanobody to create intracellularly expressed constructs capable of selectively degrading assembled proteins. We evaluated this approach against green fluorescent protein-tagged histone 2B (H2B-GFP) and tau, a protein that undergoes pathological aggregation in Alzheimer's and other neurodegenerative diseases. RING-nanobody degraders prevented or reversed tau aggregation in culture and in vivo, with minimal impact on monomeric tau. This approach may have therapeutic potential for the many disorders driven by intracellular protein aggregation.

DOI: https://doi.org/10.1126/science.adp5186
Life Sci Alliance. 2024 Nov;pii: e202402681. [Epub ahead of print]7(11):

Regulation of proteostasis by sleep through autophagy in Drosophila models of Alzheimer's disease.

Natalie Ortiz-Vega, Amanda G Lobato, Tijana Canic, Yi Zhu, Stanislav Lazopulo, Sheyum Syed, R Grace Zhai.

Sleep and circadian rhythm dysfunctions are common clinical features of Alzheimer's disease (AD). Increasing evidence suggests that in addition to being a symptom, sleep disturbances can also drive the progression of neurodegeneration. Protein aggregation is a pathological hallmark of AD; however, the molecular pathways behind how sleep affects protein homeostasis remain elusive. Here we demonstrate that sleep modulation influences proteostasis and the progression of neurodegeneration in Drosophila models of tauopathy. We show that sleep deprivation enhanced Tau aggregational toxicity resulting in exacerbated synaptic degeneration. In contrast, sleep induction using gaboxadol led to reduced toxic Tau accumulation in neurons as a result of modulated autophagic flux and enhanced clearance of ubiquitinated Tau, suggesting altered protein processing and clearance that resulted in improved synaptic integrity and function. These findings highlight the complex relationship between sleep and regulation of protein homeostasis and the neuroprotective potential of sleep-enhancing therapeutics to slow the progression or delay the onset of neurodegeneration.

DOI: https://doi.org/10.26508/lsa.202402681
Glia. 2024 Sep 03.

DNAJB6 is expressed in neurons and oligodendrocytes of the human brain.

Jónvá Hentze, Jonas Folke, Susana Aznar, Pia Nyeng, Tomasz Brudek, Christian Hansen.

  DNAJB6 is a suppressor of α-synuclein aggregation in vivo and in vitro. DNAJB6 is strongly expressed in the brain, and its overall protein expression is altered in neurodegenerative conditions such as Parkinson's Disease (PD) and Multiple System Atrophy (MSA). These two diseases are characterized by accumulation of aggregated α-synuclein in neurons and oligodendrocytes, respectively. To further explore this, we employed post-mortem normal human brain material to investigate the regional and cell type specific protein expression of DNAJB6. We found that the DNAJB6 protein is ubiquitously expressed across various regions of the brain. Notably, we demonstrate for the first time that DNAJB6 is present in nearly half (41%-53%) of the oligodendrocyte population and in the majority (68%-80%) of neurons. However, DNAJB6 was only sparsely present in other cell types such as astrocytes and microglia. Given that α-synuclein aggregation in oligodendrocytes is a hallmark of MSA, we investigated DNAJB6 presence in MSA brains compared to control brains. We found no significant difference in the percentage of oligodendrocytes where DNAJB6 was present in MSA brains relative to control brains. In conclusion, our results reveal an expression of the DNAJB6 protein across various regions of the human brain, and that DNAJB6 is almost exclusively present in neurons and oligodendrocytes. Since prior studies have shown that PD and MSA brains have altered levels of DNAJB6 relative to control brains, DNAJB6 may be an interesting target for drug development.

Keywords:  DNAJB6; chaperones; clinical samples; human brain; oligodendrocytes; α‐synuclein

DOI:  https://doi.org/10.1002/glia.24615
J Biol Chem. 2024 Aug 28. pii: S0021-9258(24)02231-2. [Epub ahead of print] 107730

Alzheimer's Disease Seeded Tau Forms Paired Helical Filaments Yet Lacks Seeding Potential.

Pu Duan, Aurelio J Dregni, Hong Xu, Lakshmi Changolkar, Virginia M-Y Lee, Edward B Lee, Mei Hong.

Alzheimer's disease (AD) and many other neurodegenerative diseases are characterized by pathological aggregation of the protein tau. These tau aggregates spread in a stereotypical spatiotemporal pattern in the brain of each disease, suggesting that the misfolded tau can recruit soluble monomers to adopt the same pathological structure. To investigate whether recruited tau indeed adopts the same structure and properties as the original seed, here we template recombinant full-length 0N3R tau, 0N4R tau, and an equimolar mixture of the two using sarkosyl-insoluble tau extracted from AD brain and determine the structures of the resulting fibrils using cryoelectron microscopy. We show that these cell-free amplified tau fibrils adopt the identical molecular structure as the AD paired-helical filament (PHF) but are unable to template additional monomers. Therefore, the PHF structure alone is insufficient for defining the pathological properties of AD tau, and other biochemical components such as tau posttranslational modifications, other proteins, polyanionic cofactors, and salt are required for the prion-like serial propagation of tauopathies.

DOI: https://doi.org/10.1016/j.jbc.2024.107730
J Transl Med. 2024 Sep 02. 22(1): 816

Tilorone mitigates the propagation of α-synucleinopathy in a midbrain-like organoid model.

Qi Zhang, Meng Liu, Yue Xu, Juhyung Lee, Brothely Jones, Bing Li, Wenwei Huang, Yihong Ye, Wei Zheng.

  BACKGROUND: Parkinson's disease (PD) is a neurodegenerative condition characterized by the loss of dopaminergic neurons and the accumulation of Lewy-body protein aggregates containing misfolded α-synuclein (α-syn) in a phosphorylated form. The lack of effective models for drug screens has hindered drug development studies for PD. However, the recent development of in vitro brain-like organoids provides a new opportunity for evaluating therapeutic agents to slow the progression of this chronic disease.METHODS: In this study, we used a 3D brain-like organoid model to investigate the potential of repurposing Tilorone, an anti-viral drug, for impeding the propagation of α-synucleinopathy. We assessed the effect of Tilorone on the uptake of fluorescently labeled α-syn preformed fibrils (sPFF) and sPFF-induced apoptosis using confocal microscopy. We also examined Tilorone's impact on the phosphorylation of endogenous α-syn induced by pathogenic sPFF by immunoblotting midbrain-like organoid extracts. Additionally, quantitative RT-PCR and proteomic profiling of sPFF-treated organoids were conducted to evaluate the global impact of Tilorone treatment on tissue homeostasis in the 3D organoid model.
RESULTS: Tilorone inhibits the uptake of sPFF in both mouse primary neurons and human midbrain-like organoids. Tilorone also reduces the phosphorylation of endogenous α-syn induced by pathogenic α-syn fibrils and mitigates α-syn fibril-induced apoptosis in midbrain-like organoids. Proteomic profiling of fibril-treated organoids reveals substantial alterations in lipid homeostasis by α-syn fibrils, which are reversed by Tilorone treatment. Given its safety profile in clinics, Tilorone may be further developed as a therapeutic intervention to alleviate the propagation of synucleinopathy in PD patients.

Keywords:  Drug preclinical development; Midbrain-like organoid; Parkinson’s disease; Tilorone; α-synuclein

DOI:  https://doi.org/10.1186/s12967-024-05551-7
bioRxiv. 2024 Aug 19. pii: 2024.08.19.608477. [Epub ahead of print]

Molecular Visualization of Neuronal TDP43 Pathology In Situ.

Amanda L Erwin, Matthew L Chang, Martin G Fernandez, Durga Attili, Jennifer E Russ, Renaldo Sutanto, Emile S Pinarbasi, Michael Bekier, Tyler S Brant, Terry Hahn, Megan Dykstra, Dafydd Thomas, Xingli Li, Ryan D Baldridge, Elizabeth M H Tank, Sami J Barmada, Shyamal Mosalaganti.

Nuclear exclusion and cytoplasmic accumulation of the RNA-binding protein TDP43 are characteristic of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Despite this, the origin and ultrastructure of cytosolic TDP43 deposits remain unknown. Accumulating evidence suggests that abnormal RNA homeostasis can drive pathological TDP43 mislocalization, enhancing RNA misprocessing due to loss of nuclear TDP43 and engendering a cycle that ends in cell death. Here, we show that adding small monovalent oligonucleotides successfully recapitulates pathological TDP43 mislocalization and aggregation in iPSC-derived neurons (iNeurons). By employing a multimodal in situ cryo-correlative light and electron microscopy pipeline, we examine how RNA influences the localization and aggregation of TDP43 in near-native conditions. We find that mislocalized TDP43 forms ordered fibrils within lysosomes and autophagosomes in iNeurons as well as in patient tissue, and provide the first high-resolution snapshots of TDP43 aggregates in situ . In so doing, we provide a cellular model for studying initial pathogenic events underlying ALS, FTLD, and related TDP43-proteinopathies.

DOI: https://doi.org/10.1101/2024.08.19.608477
Front Neurosci. 2024 ;18 1420507

α-Synuclein-mediated mitochondrial translocation of cofilin-1 leads to oxidative stress and cell apoptosis in PD.

Mingmin Yan, Qian Zhang, Yu Chen, Chenyi Zhu, Dan Wang, Jie Tan, Bihua He, Qin Li, Xiaorong Deng, Yue Wan.

  Parkinson's disease (PD) is characterized by the accumulation of misfolded α-synuclein protein and the loss of dopaminergic neurons in the substantia nigra. Abnormal α-synuclein aggregates form toxic Lewy bodies, ultimately inducing neuronal injury. Mitochondrial dysfunction was reported to be involved in the neurotoxicity of α-synuclein aggregates in PD. However, the specific mechanism by which abnormal α-synuclein aggregates cause mitochondrial disorders remains poorly defined. Previously, we found that cofilin-1, a member of the actin-binding protein, regulates α-synuclein pathogenicity by promoting its aggregation and spreading in vitro and in vivo. In this study, we further investigated the effect of cofilin-1 on α-synuclein induced mitochondrial damage. We discovered that α-synuclein aggregates accelerate the translocation of cofilin-1 to mitochondria, promote its combination with the mitochondrial outer membrane receptor Tom 20, and ultimately activate the oxidative damage and apoptosis pathway in mitochondria. All these results demonstrate the important regulatory role of cofilin-1 in the mitochondrial neurotoxicity of pathological α-synuclein during the progression of PD.

Keywords:  Parkinson's disease; apoptosis; cofilin-1; mitochondria; oxidative stress; α-synuclein

DOI:  https://doi.org/10.3389/fnins.2024.1420507
Acta Biochim Biophys Sin (Shanghai). 2024 Aug 15. 56(8): 1208-1220

Glycosylation in aging and neurodegenerative diseases.

Weilong Zhang, Tian Chen, Huijuan Zhao, Shifang Ren.

  Aging, a complex biological process, involves the progressive decline of physiological functions across various systems, leading to increased susceptibility to neurodegenerative diseases. In society, demographic aging imposes significant economic and social burdens due to these conditions. This review specifically examines the association of protein glycosylation with aging and neurodegenerative diseases. Glycosylation, a critical post-translational modification, influences numerous aspects of protein function that are pivotal in aging and the pathophysiology of diseases such as Alzheimer's disease, Parkinson's disease, and other neurodegenerative conditions. We highlight the alterations in glycosylation patterns observed during aging, their implications in the onset and progression of neurodegenerative diseases, and the potential of glycosylation profiles as biomarkers for early detection, prognosis, and monitoring of these age-associated conditions, and delve into the mechanisms of glycosylation. Furthermore, this review explores their role in regulating protein function and mediating critical biological interactions in these diseases. By examining the changes in glycosylation profiles associated with each part, this review underscores the potential of glycosylation research as a tool to enhance our understanding of aging and its related diseases.

Keywords:  aging; glycosylation; neurodegenerative diseases

DOI:  https://doi.org/10.3724/abbs.2024136
ACS Chem Neurosci. 2024 Sep 02.

Nanoscale Structural Characterization of Amyloid β 1-42 Oligomers and Fibrils Grown in the Presence of Fatty Acids.

Kiryl Zhaliazka, Dmitry Kurouski.

  Mono- and polyunsaturated fatty acids (FAs) are broadly used as food supplements. However, their effect on the aggregation of amyloidogenic proteins remains unclear. In this study, we investigated the effect of a large number of mono- and polyunsaturated, as well as fully saturated FAs on the aggregation of amyloid β1-42 (Aβ1-42) peptide. A progressive aggregation of this peptide is the expected molecular cause of Alzheimer's disease (AD), one of the most common neurodegenerative pathologies in the world. We found that arachidonic and stearic acids delayed the aggregation of Aβ1-42. Using Nano-Infrared spectroscopy, we found that FAs caused very little if any changes in the secondary structure of Aβ1-42 oligomers and fibrils formed at different stages of protein aggregation. However, the analyzed mono- and polyunsaturated, as well as fully saturated FAs uniquely altered the toxicity of Aβ1-42 fibrils. We found a direct relationship between the degree of FAs unsaturation and toxicity of Aβ1-42 fibrils formed in their presence. Specifically, with an increase in the degree of unsaturation, the toxicity Aβ1-42/FA fibrils increased. These results indicate that fully saturated or monounsaturated FAs could be used to decrease the toxicity of amyloid aggregates and, consequently, decelerate the development of AD.

Keywords:  AFM-IR; amyloid β1−42; fibrils; oligomers; polyunsaturated fatty acids

DOI:  https://doi.org/10.1021/acschemneuro.4c00275
PLoS One. 2024 ;19(8): e0308521

A charged tail on anti-α-Synuclein antibodies does not enhance their affinity to α-Synuclein fibrils.

Inga Petersen, Ana Godec, Farahnaz Ranjbarian, Anders Hofer, Claudio Mirabello, Greta Hultqvist.

The aggregation of α-Synuclein (αSyn) is strongly linked to neuronal death in Parkinson's disease and other synucleinopathies. The spreading of aggregated αSyn between neurons is at least partly dependent on electrostatic interactions between positively charged stretches on αSyn fibrils and the negatively charged heparan sulphate proteoglycans on the cell surface. To date there is still no therapeutic option available that could halt the progression of Parkinson's disease and one of the major limitations is likely the relatively low proportion of αSyn aggregates accessible to drugs in the extracellular space. Here, we investigated whether a negatively charged peptide tail fused to the αSyn aggregate-specific antibodies SynO2 and 9E4 could enhance the antibodies' avidity to αSyn aggregates in order to improve their potential therapeutic effect through inhibiting cell-to-cell spreading and enhancing the clearance of extracellular aggregates. We performed ELISAs to test the avidity to αSyn aggregates of both monovalent and bivalent antibody formats with and without the peptide tail. Our results show that the addition of the negatively charged peptide tail decreased the binding strength of both antibodies to αSyn aggregates at physiological salt conditions, which can likely be explained by intermolecular repulsions between the tail and the negatively charged C-terminus of αSyn. Additionally, the tail might interact with the paratopes of the SynO2 antibody abolishing its binding to αSyn aggregates. Conclusively, our peptide tail did not fulfil the required characteristics to improve the antibodies' binding to αSyn aggregates. Fine-tuning the design of the peptide tail to avoid its interaction with the antibodies' CDR and to better mimic relevant characteristics of heparan sulphates for αSyn aggregate binding may help overcome the limitations observed in this study.

DOI: https://doi.org/10.1371/journal.pone.0308521
J Biol Chem. 2024 Sep 02. pii: S0021-9258(24)02243-9. [Epub ahead of print] 107742

alpha-synuclein, autophagy-lysosomal pathway, and Lewy bodies: mutations, propagation, aggregation, and the formation of inclusions.

Armin Bayati, Peter S McPherson.

Research into the pathophysiology of Parkinson's disease (PD) is a fast-paced pursuit, with new findings about PD and other synucleinopathies being made each year. The involvement of various lysosomal proteins, such as TFEB, TMEM175, GBA, and LAMP1/2, marks the rising awareness about the importance of lysosomes in PD and other neurodegenerative disorders. This, along with recent developments regarding the involvement of microglia and the immune system in neurogenerative diseases, has brought about a new era in neurodegeneration: the role of proinflammatory cytokines on the nervous system, and their downstream effects on mitochondria, lysosomal degradation, and autophagy. More effort is needed to understand the interplay between neuroimmunology and disease mechanisms, as many of the mechanisms remain enigmatic. α-synuclein, a key protein in PD and the main component of Lewy bodies, sits at the nexus between lysosomal degradation, autophagy, cellular stress, neuroimmunology, PD pathophysiology, and disease progression. This review revisits some fundamental knowledge about PD while capturing some of the latest trends in PD research, specifically as it relates to α-synuclein.

DOI: https://doi.org/10.1016/j.jbc.2024.107742
Cell Mol Life Sci. 2024 Aug 30. 81(1): 377

Novel C. elegans models of Lewy body disease reveal pathological protein interactions and widespread miRNA dysregulation.

Rongzhen Li, Xiaobing Huang, Linjing Shen, Tianjiao Zhang, Ning Liu, Xiangqing Hou, Garry Wong.

  Lewy body diseases (LBD) comprise a group of complex neurodegenerative conditions originating from accumulation of misfolded alpha-synuclein (α-syn) in the form of Lewy bodies. LBD pathologies are characterized by α-syn deposition in association with other proteins such as Amyloid β (Aβ), Tau, and TAR-DNA-binding protein. To investigate the complex interactions of these proteins, we constructed 2 novel transgenic overexpressing (OE) C. elegans strains (α-synA53T;Taupro-agg (OE) and α-synA53T;Aβ1-42;Taupro-agg (OE)) and compared them with previously established Parkinson's, Alzheimer's, and Lewy Body Dementia disease models. The LBD models presented here demonstrate impairments including uncoordinated movement, egg-laying deficits, altered serotonergic and cholinergic signaling, memory and posture deficits, as well as dopaminergic neuron damage and loss. Expression levels of total and prone to aggregation α-syn protein were increased in α-synA53T;Aβ1-42 but decreased in α-synA53T;Taupro-agg animals when compared to α-synA53T animals suggesting protein interactions. These alterations were also observed at the mRNA level suggesting a pre-transcriptional mechanism. miRNA-seq revealed that cel-miR-1018 was upregulated in LBD models α-synA53T, α-synA53T;Aβ1-42, and α-synA53T;Taupro-agg compared with WT. cel-miR-58c was upregulated in α-synA53T;Taupro-agg but downregulated in α-synA53T and α-synA53T;Aβ1-42 compared with WT. cel-miR-41-3p and cel-miR-355-5p were significantly downregulated in 3 LBD models. Our results obtained in a model organism provide evidence of interactions between different pathological proteins and alterations in specific miRNAs that may further exacerbate or ameliorate LBD pathology.

Keywords:  Amyloid β; Parkinson’s disease; TAR-DNA-binding protein 43; Tau protein; α-Synuclein

DOI:  https://doi.org/10.1007/s00018-024-05383-0
Nutr Neurosci. 2024 Sep 03. 1-13

Basic approach on the protective effects of hesperidin and naringin in Alzheimer's disease.

Müjgan Kuşi, Eda Becer, Hafize Seda Vatansever.

  OBJECTIVES: Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive impairment. This situation imposes a great burden on individuals, both economically and socially. Today, an effective method for treating the disease and protective approach to tau accumulation has not been developed yet. Studies have been conducted on the effects of hesperidin and naringin flavonoids found in citrus fruits on many diseases.METHODS: In this review, the pathophysiology of AD is defined, and the effects of hesperidin and naringin on these factors are summarized.
RESULTS: Studies have shown that both components may potentially affect AD due to their antioxidative and anti-inflammatory properties. Based on these effects of the components, it has been shown that they may have ameliorative effects on Aβ, α-synuclein aggregation, tau pathology, and cognitive functions in the pathophysiology of AD.
DISCUSSION: There are studies suggesting that hesperidin and naringin may be effective in the prevention/treatment of AD. When these studies are examined, it is seen that more studies should be conducted on the subject.

Keywords:  Alzheimer’s disease; Aβ aggregation; antiapoptotic effect; hesperidin; inflammation; naringin; neuroprotective effect; oxidative stress

DOI:  https://doi.org/10.1080/1028415X.2024.2397136
bioRxiv. 2024 Jul 23. pii: 2024.07.22.604618. [Epub ahead of print]

Phosphorylation at serine 214 correlates with tau seeding activity in an age-dependent manner in two mouse models for tauopathies and is required for tau transsynaptic propagation.

Pablo Martinez, Nur Jury-Garfe, Henika Patel, Yanwen You, Abigail Perkins, Yingjan You, Audrey Lee-Gosselin, Ruben Vidal, Cristian A Lasagna-Reeves.

Pathological aggregation and propagation of hyperphosphorylated and aberrant forms of tau are critical features of the clinical progression of Alzheimer's disease and other tauopathies. To better understand the correlation between these pathological tau species and disease progression, we profiled the temporal progression of tau seeding activity and the levels of various phospho- and conformational tau species in the brains of two mouse models of human tauopathies. Our findings indicate that tau seeding is an early event that occurs well before the appearance of AT8-positive NFT. Specifically, we observed that tau phosphorylation in serine 214 (pTau-Ser214) positively correlates to tau seeding activity during disease progression in both mouse models. Furthermore, we found that the histopathology of pTau-Ser214 appears much earlier and has a distinct pattern and compartmentalization compared to the pathology of AT8, demonstrating the diversity of tau species within the same region of the brain. Importantly, we also observed that preventing the phosphorylation of tau at Ser214 significantly decreases tau propagation in mouse primary neurons, and seeding activity in a Drosophila model of tauopathy, suggesting a role for this tau phosphorylation in spreading pathological forms of tau. Together, these results suggest that the diverse spectrum of soluble pathological tau species could be responsible for the distinct pathological properties of tau and that it is critical to dissect the nature of the tau seed in the context of disease progression.

DOI: https://doi.org/10.1101/2024.07.22.604618