bims-proned 2024-08-11 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2024‒08‒11
ten papers selected by
Verena Kohler, Umeå University

Acute sleep deprivation in mice generates protein pathology consistent with neurodegenerative diseases.
DNAJA2 and Hero11 mediate similar conformational extension and aggregation suppression of TDP-43.
Protein modification in neurodegenerative diseases.
Liquid-liquid phase separation of alpha-synuclein increases the structural variability of fibrils formed during amyloid aggregation.
ProSAAS is preferentially up-regulated during homeostatic scaling and reduces amyloid plaque burden in the 5xFAD mouse hippocampus.
Characterization of Olive Oil Phenolic Extracts and Their Effects on the Aggregation of the Alzheimer's Amyloid-β Peptide and Tau.
Structure-Activity Relationship of Fluorinated Benzenesulfonamides as Inhibitors of Amyloid-β Aggregation.
Axonopathy Underlying Amyotrophic Lateral Sclerosis: Unraveling Complex Pathways and Therapeutic Insights.
Tau in neurodegenerative diseases: molecular mechanisms, biomarkers, and therapeutic strategies.
Repurposing Anidulafungin for Alzheimer's Disease via Fragment-Based Drug Discovery.

Front Neurosci. 2024 ;18 1436966

Acute sleep deprivation in mice generates protein pathology consistent with neurodegenerative diseases.

Rachel K Rowe, Philip Schulz, Ping He, Grant S Mannino, Mark R Opp, Michael R Sierks.

  Introduction: Insufficient or disturbed sleep is strongly associated with adverse health conditions, including various neurodegenerative disorders. While the relationship between sleep and neurodegenerative disease is likely bidirectional, sleep disturbances often predate the onset of other hallmark clinical symptoms. Neuronal waste clearance is significantly more efficient during sleep; thus, disturbed sleep may lead to the accumulation of neuronal proteins that underlie neurodegenerative diseases. Key pathological features of neurodegenerative diseases include an accumulation of misfolded or misprocessed variants of amyloid beta (Aβ), tau, alpha synuclein (α-syn), and TarDNA binding protein 43 (TDP-43). While the presence of fibrillar protein aggregates of these neuronal proteins are characteristic of neurodegenerative diseases, the presence of small soluble toxic oligomeric variants of these different proteins likely precedes the formation of the hallmark aggregates.Methods: We hypothesized that sleep deprivation would lead to accumulation of toxic oligomeric variants of Aβ, tau, α-syn, and TDP-43 in brain tissue of wild-type mice. Adult mice were subjected to 6 h of sleep deprivation (zeitgeber 0-6) for 5 consecutive days or were left undisturbed as controls. Following sleep deprivation, brains were collected, and protein pathology was assessed in multiple brain regions using an immunostain panel of reagents selectively targeting neurodegenerative disease-related variants of Aβ, tau, α-syn, and TDP-43.
Results: Overall, sleep deprivation elevated levels of all protein variants in at least one of the brain regions of interest. The reagent PDTDP, targeting a TDP-43 variant present in Parkinson's disease, was elevated throughout the brain. The cortex, caudoputamen, and corpus callosum brain regions showed the highest accumulation of pathology following sleep deprivation.
Discussion: These data provide a direct mechanistic link between sleep deprivation, and the hallmark protein pathologies of neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases.

Keywords:  Alzheimer’s disease; neurodegeneration; pathology; sleep; sleep disruption

DOI:  https://doi.org/10.3389/fnins.2024.1436966
RNA. 2024 Aug 08. pii: rna.080165.124. [Epub ahead of print]

DNAJA2 and Hero11 mediate similar conformational extension and aggregation suppression of TDP-43.

Andy Y W Lam, Kotaro Tsuboyama, Hisashi Tadakuma, Yukihide Tomari.

  Many RNA binding proteins (RBPs) contain low-complexity domains (LCDs) with prion-like compositions. These long intrinsically disordered regions regulate their solubility, contributing to their physiological roles in RNA processing and organization. However, this also makes these RBPs prone to pathological misfolding and aggregation that are characteristic of neurodegenerative diseases. For example, TAR DNA-binding protein 43 (TDP-43) forms pathological aggregates associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). While molecular chaperones are well-known suppressors of these aberrant events, we recently reported that highly disordered, hydrophilic and charged heat-resistant obscure (Hero) proteins may have similar effects. Specifically, Hero proteins can maintain the activity of other proteins from denaturing conditions in vitro, while their overexpression can suppress cellular aggregation and toxicity associated with aggregation-prone proteins. However, it is unclear how these protective effects are achieved. Here, we utilized single-molecule FRET to monitor the conformations of the aggregation-prone prion-like LCD of TDP-43. While we observed high conformational heterogeneity in wild-type LCD, the ALS-associated mutation A315T promoted collapsed conformations. In contrast, an Hsp40 chaperone, DNAJA2, and a Hero protein, Hero11 stabilized extended states of the LCD, consistent with their ability to suppress the aggregation of TDP-43. Our results link single-molecule effects on conformation to macro effects on bulk aggregation, where a Hero protein, like a chaperone, can maintain the conformational integrity of a client protein to prevent its aggregation.

Keywords:  Hero protein; TAR DNA-binding protein 43; chaperone; intrinsically disordered protein; single-molecule FRET

DOI:  https://doi.org/10.1261/rna.080165.124
MedComm (2020). 2024 Aug;5(8): e674

Protein modification in neurodegenerative diseases.

Shahin Ramazi, Maedeh Dadzadi, Mona Darvazi, Nasrin Seddigh, Abdollah Allahverdi.

  Posttranslational modifications play a crucial role in governing cellular functions and protein behavior. Researchers have implicated dysregulated posttranslational modifications in protein misfolding, which results in cytotoxicity, particularly in neurodegenerative diseases such as Alzheimer disease, Parkinson disease, and Huntington disease. These aberrant posttranslational modifications cause proteins to gather in certain parts of the brain that are linked to the development of the diseases. This leads to neuronal dysfunction and the start of neurodegenerative disease symptoms. Cognitive decline and neurological impairments commonly manifest in neurodegenerative disease patients, underscoring the urgency of comprehending the posttranslational modifications' impact on protein function for targeted therapeutic interventions. This review elucidates the critical link between neurodegenerative diseases and specific posttranslational modifications, focusing on Tau, APP, α-synuclein, Huntingtin protein, Parkin, DJ-1, and Drp1. By delineating the prominent aberrant posttranslational modifications within Alzheimer disease, Parkinson disease, and Huntington disease, the review underscores the significance of understanding the interplay among these modifications. Emphasizing 10 key abnormal posttranslational modifications, this study aims to provide a comprehensive framework for investigating neurodegenerative diseases holistically. The insights presented herein shed light on potential therapeutic avenues aimed at modulating posttranslational modifications to mitigate protein aggregation and retard neurodegenerative disease progression.

Keywords:  SUMOylation; immune system; neurodegenerative diseases; posttranslational modifications

DOI:  https://doi.org/10.1002/mco2.674
FEBS J. 2024 Aug 08.

Liquid-liquid phase separation of alpha-synuclein increases the structural variability of fibrils formed during amyloid aggregation.

Mantas Ziaunys, Darius Sulskis, Dominykas Veiveris, Aurimas Kopustas, Ruta Snieckute, Kamile Mikalauskaite, Andrius Sakalauskas, Marijonas Tutkus, Vytautas Smirnovas.

  Protein liquid-liquid phase separation (LLPS) is a rapidly emerging field of study on biomolecular condensate formation. In recent years, this phenomenon has been implicated in the process of amyloid fibril formation, serving as an intermediate step between the native protein transition into their aggregated state. The formation of fibrils via LLPS has been demonstrated for a number of proteins related to neurodegenerative disorders, as well as other amyloidoses. Despite the surge in amyloid-related LLPS studies, the influence of protein condensate formation on the end-point fibril characteristics is still far from fully understood. In this work, we compare alpha-synuclein aggregation under different conditions, which promote or negate its LLPS and examine the differences between the formed aggregates. We show that alpha-synuclein phase separation generates a wide variety of assemblies with distinct secondary structures and morphologies. The LLPS-induced structures also possess higher levels of toxicity to cells, indicating that biomolecular condensate formation may be a critical step in the appearance of disease-related fibril variants.

Keywords:  aggregation; alpha‐synuclein; fibril structure; liquid–liquid phase separation

DOI:  https://doi.org/10.1111/febs.17244
J Neurochem. 2024 Aug 08.

ProSAAS is preferentially up-regulated during homeostatic scaling and reduces amyloid plaque burden in the 5xFAD mouse hippocampus.

Samira Mitias, Nicholas Schaffer, Saaya Nair, Chelsea Hook, Iris Lindberg.

  The accumulation of β-amyloid in Alzheimer's disease greatly impacts neuronal health and synaptic function. To maintain network stability in the face of altered synaptic activity, neurons engage a feedback mechanism termed homeostatic scaling; however, this process is thought to be disrupted during disease progression. Previous proteomics studies have shown that one of the most highly regulated proteins in cell culture models of homeostatic scaling is the small secretory chaperone proSAAS. Our prior work has shown that proSAAS exhibits anti-aggregant behavior against alpha-synuclein and β-amyloid fibrillation in vitro and is up-regulated in cell models of proteostatic stress. However, the specific role that this protein might play in homeostatic scaling, and its anti-aggregant role in Alzheimer's progression, is not clear. To learn more about the role of proSAAS in maintaining hippocampal proteostasis, we compared its expression in a primary neuron model of homeostatic scaling to other synaptic components using western blotting and qPCR, revealing that proSAAS protein responses to homeostatic up- and down-regulation were significantly higher than those of two other synaptic vesicle components, 7B2 and carboxypeptidase E. However, proSAAS mRNA expression was static, suggesting translational control and/or altered protein degradation. ProSAAS was readily released upon depolarization of differentiated hippocampal cultures, supporting its synaptic localization. Immunohistochemical analysis demonstrated abundant proSAAS within the mossy fiber layer of the hippocampus in both wild-type and 5xFAD mice; in the latter, proSAAS was also concentrated around amyloid plaques. Importantly, overexpression of proSAAS in the CA1 region via stereotaxic injection of proSAAS-encoding AAV2/1 significantly decreased amyloid plaque burden in 5xFAD mice. We hypothesize that dynamic changes in proSAAS expression play a critical role in hippocampal proteostatic processes, both in the context of normal homeostatic plasticity and in the control of protein aggregation during Alzheimer's disease progression.

Keywords:  Alzheimer's; Pcsk1n; hippocampus; homeostatic scaling; proSAAS; proteostasis

DOI:  https://doi.org/10.1111/jnc.16193
ACS Omega. 2024 Jul 30. 9(30): 32557-32578

Characterization of Olive Oil Phenolic Extracts and Their Effects on the Aggregation of the Alzheimer's Amyloid-β Peptide and Tau.

Bakri Alaziqi, Liam Beckitt, David J Townsend, Jasmine Morgan, Rebecca Price, Alana Maerivoet, Jillian Madine, David Rochester, Geoffrey Akien, David A Middleton.

The dietary consumption of extra virgin olive oil (EVOO) is believed to slow the progression of Alzheimer's disease (AD) symptoms. Its protective mechanisms are unclear, but specific EVOO phenolic compounds can individually impede the aggregation of amyloid-β (Aβ) peptides and the microtubule-associated protein tau, two important pathological manifestations of AD. It is unknown, however, whether the numerous and variable phenolic compounds that are consumed in dietary EVOO can collectively alter tau and Aβ aggregation as effectively as the individual compounds. The activity of these complex mixtures against Aβ and tau may be moderated by competition between active and nonactive phenolic components and by extensive derivatizations and isomerization. Here, phenolic mixtures extracted from two different EVOO sources are characterized and tested for how they modulate the aggregation of Aβ40 peptide and tau peptides in vitro. The chromatographic and NMR analysis of Greek and Saudi Arabian EVOO phenolic extracts reveals that they have different concentration profiles, and over 30 compounds are identified. Thioflavin T fluorescence and circular dichroism measurements show that relatively low concentrations (<20 μg/mL) of the Greek and Saudi extracts reduce the rate of Aβ40 aggregation and fibril mass, despite the extracts having different phenolic profiles. By contrast, the Greek extract reduces the rate of tau aggregation only at very high phenolic concentrations (>100 μg/mL). Most compounds in the extracts bind to preformed Aβ40 fibrils and release soluble Aβ oligomers that are mildly toxic to SH-SY5Y cells. Much higher (500 μg/mL) extract concentrations are required to remodel tau filaments into oligomers, and a minimal binding of phenolic compounds to the preformed filaments is observed. It is concluded that EVOO extracts having different phenol profiles are similarly capable of modulating Aβ40 aggregation and fibril morphology in vitro at relatively low concentrations but are less efficient at modulating tau aggregation. Over 2 M tonnes of EVOO are consumed globally each year as part of the Mediterranean diet, and the results here provide motivation for further clinical interrogation of the antiaggregation properties of EVOO as a potential protective mechanism against AD.

DOI: https://doi.org/10.1021/acsomega.4c01281
Chemistry. 2024 Aug 07. e202402330

Structure-Activity Relationship of Fluorinated Benzenesulfonamides as Inhibitors of Amyloid-β Aggregation.

Mantas Žvirblis, Andrius Sakalauskas, Saeid Hadi Ali Janvand, Virginija Dudutienė, Mantas Žiaunys, Rūta Sniečkutė, Daniel E Otzen, Vytautas Smirnovas, Daumantas Matulis.

  Amyloid-beta aggregation is considered one of the factors influencing the onset of the Alzheimer's disease. Early prevention of such aggregation should alleviate disease condition by applying small molecule compounds that shift the aggregation equilibrium toward the soluble form of the peptide or slow down the process. We have discovered that fluorinated benzenesulfonamides of particular structure slowed the amyloid-beta peptide aggregation process by more than three-fold. We synthesized a series of ortho-para and meta-para double-substituted fluorinated benzenesulfonamides that inhibited the aggregation process to a variable extent yielding a detailed picture of the structure-activity relationship. Analysis of compound chemical structure effect on aggregation in artificial cerebrospinal fluid showed the necessity to arrange the benzenesulfonamide, hydrophobic substituent, and benzoic acid in a particular way. The amyloid beta peptide aggregate fibril structures varied in cross-sectional height depending on the applied inhibitor indicating the formation of a complex with the compound. Application of selected inhibitors increased the survivability of cells affected by the amyloid beta peptide. Such compounds may be developed as drugs against Alzheimer's disease.

Keywords:  Alzheimer's disease; amyloid beta peptide; amyloid fibrils; artificial cerebrospinal fluid; benzenesulfonamide

DOI:  https://doi.org/10.1002/chem.202402330
Neurosci Bull. 2024 Aug 04.

Axonopathy Underlying Amyotrophic Lateral Sclerosis: Unraveling Complex Pathways and Therapeutic Insights.

Tongshu Luan, Qing Li, Zhi Huang, Yu Feng, Duo Xu, Yujie Zhou, Yiqing Hu, Tong Wang.

  Amyotrophic Lateral Sclerosis (ALS) is a complex neurodegenerative disorder characterized by progressive axonopathy, jointly leading to the dying back of the motor neuron, disrupting both nerve signaling and motor control. In this review, we highlight the roles of axonopathy in ALS progression, driven by the interplay of multiple factors including defective trafficking machinery, protein aggregation, and mitochondrial dysfunction. Dysfunctional intracellular transport, caused by disruptions in microtubules, molecular motors, and adaptors, has been identified as a key contributor to disease progression. Aberrant protein aggregation involving TDP-43, FUS, SOD1, and dipeptide repeat proteins further amplifies neuronal toxicity. Mitochondrial defects lead to ATP depletion, oxidative stress, and Ca2+ imbalance, which are regarded as key factors underlying the loss of neuromuscular junctions and axonopathy. Mitigating these defects through interventions including neurotrophic treatments offers therapeutic potential. Collaborative research efforts aim to unravel ALS complexities, opening avenues for holistic interventions that target diverse pathological mechanisms.

Keywords:  Amyotrophic lateral sclerosis; Axon trafficking; Axonopathy; Mitochondrial defect; Neurotrophic factor; Protein aggregation

DOI:  https://doi.org/10.1007/s12264-024-01267-2
Transl Neurodegener. 2024 Aug 06. 13(1): 40

Tau in neurodegenerative diseases: molecular mechanisms, biomarkers, and therapeutic strategies.

Xingyu Zhang, Jiangyu Wang, Zhentao Zhang, Keqiang Ye.

  The deposition of abnormal tau protein is characteristic of Alzheimer's disease (AD) and a class of neurodegenerative diseases called tauopathies. Physiologically, tau maintains an intrinsically disordered structure and plays diverse roles in neurons. Pathologically, tau undergoes abnormal post-translational modifications and forms oligomers or fibrous aggregates in tauopathies. In this review, we briefly introduce several tauopathies and discuss the mechanisms mediating tau aggregation and propagation. We also describe the toxicity of tau pathology. Finally, we explore the early diagnostic biomarkers and treatments targeting tau. Although some encouraging results have been achieved in animal experiments and preclinical studies, there is still no cure for tauopathies. More in-depth basic and clinical research on the pathogenesis of tauopathies is necessary.

Keywords:  Aggregation; Alzheimer’s disease; Biomarkers; Propagation; Tau; Tauopathies

DOI:  https://doi.org/10.1186/s40035-024-00429-6
ACS Chem Neurosci. 2024 Aug 03.

Repurposing Anidulafungin for Alzheimer's Disease via Fragment-Based Drug Discovery.

Siqi Xie, Yumei Liang, Yang Song, Tingting Li, Jianping Jia.

  The misfolding and aggregation of beta-amyloid (Aβ) peptides have been implicated as key pathogenic events in the early stages of Alzheimer's disease (AD). Inhibiting Aβ aggregation represents a potential disease-modifying therapeutic approach to AD treatment. Previous studies have identified various molecules that inhibit Aβ aggregation, some of which share common chemical substructures (fragments) that may be key to their inhibitory activity. Employing fragment-based drug discovery (FBDD) methods may facilitate the identification of these fragments, which can subsequently be used to screen new inhibitors and provide leads for further drug development. In this study, we used an in silico FBDD approach to identify 17 fragment clusters that are significantly enriched among Aβ aggregation inhibitors. These fragments were then used to screen anti-infective agents, a promising drug class for repurposing against amyloid aggregation. This screening process identified 16 anti-infective drugs, 5 of which were chosen for further investigation. Among the 5 candidates, anidulafungin, an antifungal compound, showed high efficacy in inhibiting Aβ aggregation in vitro. Kinetic analysis revealed that anidulafungin selectively blocks the primary nucleation step of Aβ aggregation, substantially delaying Aβ fibril formation. Cell viability assays demonstrated that anidulafungin can reduce the toxicity of oligomeric Aβ on BV2 microglia cells. Molecular docking simulations predicted that anidulafungin interacted with various Aβ species, including monomers, oligomers, and fibrils, potentially explaining its activity against Aβ aggregation and toxicity. This study suggests that anidulafungin is a potential drug to be repurposed for AD, and FBDD is a promising approach for discovering drugs to combat Aβ aggregation.

Keywords:  Alzheimer’s disease; aggregation inhibitors; anidulafungin; beta amyloid; drug repurposing; fragment-based drug discovery

DOI:  https://doi.org/10.1021/acschemneuro.4c00150