bims-proned 2024-07-28 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2024‒07‒28
thirteen papers selected by
Verena Kohler, Umeå University

Structural Variations of Prions and Prion-like Proteins Associated with Neurodegeneration.
Tau Protein and Tauopathies: Exploring Tau Protein-Protein and Microtubule Interactions, Cross-Interactions and Therapeutic Strategies.
Wild-Type α-Synuclein Structure and Aggregation: A Comprehensive Coarse-Grained and All-Atom Molecular Dynamics Study.
Natural products targeting amyloid-β oligomer neurotoxicity in Alzheimer's disease.
Tracking heterogenous protein aggregation at nanoscale through fluorescence correlation spectroscopy.
UNVEILING DEFECTS OF SECRETION MECHANISMS IN PARKINSON'S DISEASE.
Pro-cathepsin D prevents aberrant protein aggregation dependent on endoplasmic reticulum protein CLN6.
Are Preformed Fibrils a Model of Parkinson's Disease?
Polyamines putrescine and spermidine as modulators of protein aggregation rate: The effect on DTT-induced aggregation of α-lactalbumin.
Intracellular tau fragment droplets serve as seeds for tau fibrils.
Interaction between α-Synuclein and Bioactive Lipids: Neurodegeneration, Disease Biomarkers and Emerging Therapies.
Copper toxicity and deficiency: the vicious cycle at the core of protein aggregation in ALS.
Spatial selectivity of ATase inhibition in mouse models of Charcot-Marie-Tooth disease.

Curr Issues Mol Biol. 2024 Jun 26. 46(7): 6423-6439

Structural Variations of Prions and Prion-like Proteins Associated with Neurodegeneration.

Carter Sky Christensen, Sean Wang, Wenshu Li, Danyang Yu, Henry James Li.

  Neurodegeneration is becoming one of the leading causes of death worldwide as the population expands and grows older. There is a growing desire to understand the mechanisms behind prion proteins as well as the prion-like proteins that make up neurodegenerative diseases (NDs), including Alzheimer's disease (AD) and Parkinson's disease (PD). Both amyloid-β (Aβ) and hyperphosphorylated tau (p-tau) proteins behave in ways similar to those of the infectious form of the prion protein, PrPSc, such as aggregating, seeding, and replicating under not yet fully understood mechanisms, thus the designation of prion-like. This review aims to highlight the shared mechanisms between prion-like proteins and prion proteins in the structural variations associated with aggregation and disease development. These mechanisms largely focus on the dysregulation of protein homeostasis, self-replication, and protein aggregation, and this knowledge could contribute to diagnoses and treatments for the given NDs.

Keywords:  Alzheimer’s disease; aggregation; alpha-synuclein; amyloid beta; hyperphosphorylated tau; neurodegeneration; prion-like proteins; prions; protein homeostasis

DOI:  https://doi.org/10.3390/cimb46070384
ChemMedChem. 2024 Jul 19. e202400180

Tau Protein and Tauopathies: Exploring Tau Protein-Protein and Microtubule Interactions, Cross-Interactions and Therapeutic Strategies.

Davide Di Lorenzo.

  Tau, a microtubule-associated protein (MAP), is essential to maintaining neuronal stability and function in the healthy brain. However, aberrant modifications and pathological aggregations of Tau are implicated in various neurodegenerative disorders, collectively known as tauopathies. The most common Tauopathy is Alzheimer's Disease (AD) counting nowadays more than 60 million patients worldwide. This comprehensive review delves into the multifaceted realm of Tau protein, puzzling out its intricate involvement in both physiological and pathological roles. Emphasis is put on Tau Protein-Protein Interactions (PPIs), depicting its interaction with tubulin, microtubules and its cross-interaction with other proteins such as Aβ1-42, α-synuclein, and the chaperone machinery. In the realm of therapeutic strategies, an overview of diverse possibilities is presented with their relative clinical progresses. The focus is mostly addressed to Tau protein aggregation inhibitors including recent small molecules, short peptides and peptidomimetics with specific focus on compounds that showed a double anti aggregative activity on both Tau protein and Aβ amyloid peptide. This review amalgamates current knowledge on Tau protein and evolving therapeutic strategies, providing a comprehensive resource for researchers seeking to deepen their understanding of the Tau protein and for scientists involved in the development of new peptide-based anti-aggregative Tau compounds.

Keywords:  * Chaperone machinery * Tau in Alzheimer's Disease * Tau Therapeutic Strategies * Tau Cross-interaction * Tau Aβ aggregation inhibitors

DOI:  https://doi.org/10.1002/cmdc.202400180
J Chem Inf Model. 2024 Jul 24.

Wild-Type α-Synuclein Structure and Aggregation: A Comprehensive Coarse-Grained and All-Atom Molecular Dynamics Study.

Gabriel F Martins, Nuno Galamba.

α-Synuclein (α-syn) is a 140 amino acid intrinsically disordered protein (IDP) and the primary component of cytotoxic oligomers implicated in the etiology of Parkinson's disease (PD). While IDPs lack a stable three-dimensional structure, they sample a heterogeneous ensemble of conformations that can, in principle, be assessed through molecular dynamics simulations. However, describing the structure and aggregation of large IDPs is challenging due to force field (FF) accuracy and sampling limitations. To cope with the latter, coarse-grained (CG) FFs emerge as a potential alternative at the expense of atomic detail loss. Whereas CG models can accurately describe the structure of the monomer, less is known about aggregation. The latter is key for assessing aggregation pathways and designing aggregation inhibitor drugs. Herein, we investigate the structure and dynamics of α-syn using different resolution CG (Martini3 and Sirah2) and all-atom (Amber99sb and Charmm36m) FFs to gain insight into the differences and resemblances between these models. The dependence of the magnitude of protein-water interactions and the putative need for enhanced sampling (replica exchange) methods in CG simulations are analyzed to distinguish between force field accuracy and sampling limitations. The stability of the CG models of an α-syn fibril was also investigated. Additionally, α-syn aggregation was studied through umbrella sampling for the CG models and CG/all-atom models for an 11-mer peptide (NACore) from an amyloidogenic domain of α-syn. Our results show that despite the α-syn structures of Martini3 and Sirah2 with enhanced protein-water interactions being similar, major differences exist concerning aggregation. The Martini3 fibril is not stable, and the binding free energy of α-syn and NACore is positive, opposite to Sirah2. Sirah2 peptides in a zwitterionic form, in turn, display termini interactions that are too strong, resulting in end-to-end orientation. Sirah2, with enhanced protein-water interactions and neutral termini, provides, however, a peptide aggregation free energy profile similar to that found with all-atom models. Overall, we find that Sirah2 with enhanced protein-water interactions is suitable for studying protein-protein and protein-drug aggregation.

DOI: https://doi.org/10.1021/acs.jcim.4c00965
Eur J Med Chem. 2024 Jul 14. pii: S0223-5234(24)00564-6. [Epub ahead of print]276 116684

Natural products targeting amyloid-β oligomer neurotoxicity in Alzheimer's disease.

Priscila Baltazar Gonçalves, Ana Carolina Rennó Sodero, Yraima Cordeiro.

  Alzheimer's disease (AD) constitutes a major global health issue, characterized by progressive neurodegeneration and cognitive impairment, for which no curative treatment is currently available. Current therapeutic approaches are focused on symptom management, highlighting the critical need for disease-modifying therapy. The hallmark pathology of AD involves the aggregation and accumulation of amyloid-β (Aβ) peptides in the brain. Consequently, drug discovery efforts in recent decades have centered on the Aβ aggregation cascade, which includes the transition of monomeric Aβ peptides into toxic oligomers and, ultimately, mature fibrils. Historically, anti-Aβ strategies focused on the clearance of amyloid fibrils using monoclonal antibodies. However, substantial evidence has highlighted the critical role of Aβ oligomers (AβOs) in AD pathogenesis. Soluble AβOs are now recognized as more toxic than fibrils, directly contributing to synaptic impairment, neuronal damage, and the onset of AD. Targeting AβOs has emerged as a promising therapeutic approach to mitigate cognitive decline in AD. Natural products (NPs) have demonstrated promise against AβO neurotoxicity through various mechanisms, including preventing AβO formation, enhancing clearance mechanisms, or converting AβOs into non-toxic species. Understanding the mechanisms by which anti-AβO NPs operate is useful for developing disease-modifying treatments for AD. In this review, we explore the role of NPs in mitigating AβO neurotoxicity for AD drug discovery, summarizing key evidence from biophysical methods, cellular assays, and animal models. By discussing how NPs modulate AβO neurotoxicity across various experimental systems, we aim to provide valuable insights into novel therapeutic strategies targeting AβOs in AD.

Keywords:  Alzheimer's disease animal models; Amyloid aggregation; Anti-amyloid; Caenorhabditis elegans; Curcumin; Epigallocatechin-3-gallate; Resveratrol; Squalamine; Trodusquemine

DOI:  https://doi.org/10.1016/j.ejmech.2024.116684
Photochem Photobiol. 2024 Jul 19.

Tracking heterogenous protein aggregation at nanoscale through fluorescence correlation spectroscopy.

Bisal Halder, Shreya Ghosh, Tanmoy Khan, Subhendu Pal, Nilimesh Das, Pratik Sen.

  Various biophysical techniques have been extensively employed to study protein aggregation due to its significance. Traditionally, these methods detect aggregation at micrometer length scales and micromolar concentrations. However, unlike in vitro, protein aggregation typically occurs at nanomolar concentrations in vivo. Here, using fluorescence correlation spectroscopy (FCS), we captured bromelain aggregation at concentrations as low as ~20 nM, surpassing the detection limit of traditional methods like thioflavin T fluorescence, scattering, and fluorescence microscopy by more than one order of magnitude. Moreover, using thioflavin T fluorescence-based FCS, we have detected larger aggregates at higher bromelain concentrations, which is undetectable in FCS otherwise. Importantly, our study reveals inherent heterogeneity in bromelain aggregation, inaccessible to ensemble-averaged techniques. The presented report may provide a platform for the characterization of premature aggregates at very low protein concentrations, which are thought to be functionally significant species in protein aggregation-induced diseases.

Keywords:  bromelain; fluorescence correlation spectroscopy; heterogeneity; protein aggregation

DOI:  https://doi.org/10.1111/php.14004
J Biol Chem. 2024 Jul 24. pii: S0021-9258(24)02104-5. [Epub ahead of print] 107603

UNVEILING DEFECTS OF SECRETION MECHANISMS IN PARKINSON'S DISEASE.

Francesca Filippini, Thierry Galli.

  Neurodegenerative diseases are characterized by progressive dysfunction and loss of specific sets of neurons. While extensive research has focused on elucidating the genetic and epigenetic factors and molecular mechanisms underlying these disorders, emerging evidence highlights the critical role of secretion in the pathogenesis, possibly even onset, and progression of neurodegenerative diseases, suggesting the occurrence of non-cell-autonomous mechanisms. Secretion is a fundamental process that regulates intercellular communication, supports cellular homeostasis, and orchestrates various physiological functions in the body. Defective secretion can impair the release of neurotransmitters and other signaling molecules, disrupting synaptic transmission and compromising neuronal survival. It can also contribute to the accumulation, misfolding, and aggregation of disease-associated proteins, leading to neurotoxicity and neuronal dysfunction. In this review, we discuss the implications of defective secretion in the context of Parkinson's disease, emphasizing its role in protein aggregation, synaptic dysfunction, extracellular vesicle secretion and neuroinflammation. We propose a multiple-hit model whereby protein accumulation and secretory defects must be combined for the onset and progression of the disease.

Keywords:  Parkinson’s disease; astrocytes; extracellular vesicles; microglia; protein secretion; synapse

DOI:  https://doi.org/10.1016/j.jbc.2024.107603
Mol Genet Metab. 2024 Jul 16. pii: S1096-7192(24)00423-2. [Epub ahead of print]143(1-2): 108539

Pro-cathepsin D prevents aberrant protein aggregation dependent on endoplasmic reticulum protein CLN6.

Yuki Shiro, Syouichi Katayama, Haruka Tsukamoto, Tetsuo Yamazaki.

  We previously expressed a chimeric protein in which the small heat-shock protein αB-crystallin (αBC) is fused at its N-terminus to the C-terminus of the first transmembrane segment of the endoplasmic reticulum (ER) protein mitsugumin 23 and confirmed its localization to the ER. Moreover, overexpression of this N-terminally modified αBC was shown to prevent the aggregation of the coexpressed R120G αBC variant, which is highly aggregation-prone and associated with the hereditary myopathy αB-crystallinopathy. To uncover a molecular mechanism by which the ER-anchored αBC negatively regulates the protein aggregation, we isolated proteins that bind to the ER-anchored αBC and identified the lysosomal protease cathepsin D (CTSD) as one such interacting protein. Proteolytically active CTSD is produced by multi-step processing of pro-cathepsin D (proCTSD), which is initially synthesized in the ER and delivered to lysosomes. When overexpressed, CTSD itself prevented the coexpressed R120G αBC variant from aggregating. This anti-aggregate activity was also elicited upon overexpression of the W383C CTSD variant, which is predominantly sequestered in the ER and consequently remains unprocessed, suggesting that proCTSD, rather than mature CTSD, serves to suppress the aggregation of the R120G αBC variant. Meanwhile, overexpression of the A58V CTSD variant, which is identical to wild-type CTSD except for the Ala58Val substitution within the pro-peptide, did not suppress the protein aggregation, indicating that the integrity of the pro-peptide is required for proCTSD to exert its anti-aggregate activity. Based on our previous finding that overexpression of the ER transmembrane protein CLN6 (ceroid-lipofuscinosis, neuronal 6), identified as an interacting protein of the ER-anchored αBC, prevents the R120G αBC variant from aggregating, the CLN6-proCTSD coupling was hypothesized to underpin the functionality of proCTSD within the ER. Indeed, CTSD, when overexpressed in CLN6-depleted cells, was unable to exert its anti-aggregate activity, supporting our view. Collectively, we show here that proCTSD prevents the protein aggregation through the functional association with CLN6 in the microenvironment surrounding the ER membrane, shedding light on a novel aspect of proCTSD and its potential involvement in CTSD-related disorders characterized by the accumulation of aberrant protein aggregates.

Keywords:  Alzheimer's disease; CLN6; Cathepsin D; Endoplasmic reticulum; Neuronal ceroid Lipofuscinosis; Pro-cathepsin D; Pro-peptide

DOI:  https://doi.org/10.1016/j.ymgme.2024.108539
J Parkinsons Dis. 2024 Jul 12.

Are Preformed Fibrils a Model of Parkinson's Disease?

Amanda L Woerman, Kelvin C Luk.

   Pre-formed fibrils (PFFs) made from recombinant α-synuclein are broadly used throughout the field in cellular and animal models of Parkinson's disease. However, their ability to successfully recapitulate disease biology is a controversial topic. In this article, two researchers debate this issue with Amanda Woerman taking the view that PFFs are a model of synucleinopathy but not Parkinson's disease, while Kelvin Luk defends their use as an important tool in the field.

Keywords:  Alpha-synuclein; Parkinson’s disease; synucleinopathies

DOI:  https://doi.org/10.3233/JPD-240228
Biochimie. 2024 Jul 20. pii: S0300-9084(24)00170-6. [Epub ahead of print]

Polyamines putrescine and spermidine as modulators of protein aggregation rate: The effect on DTT-induced aggregation of α-lactalbumin.

Dmitriy A Kara, Vera A Borzova, Svetlana G Roman, Sergey Yu Kleymenov, Natalia A Chebotareva.

  Protein aggregation is undesirable for cells due to its possible toxicity, and is also undesirable in biotechnology and pharmaceuticals. Polyamines are known to be capable of both suppressing and stimulating protein aggregation. In the present work polyamines (spermidine, putrescine) have been shown to alter the pathway of α-lactalbumin aggregation induced by dithiothreitol, leading to the formation of larger protein particles during the initial stages of aggregation and promoting the later stage of sticking of aggregates. According to the aggregation kinetics data, polyamines accelerate protein aggregation in a concentration-dependent manner, with a maximum at 50 mM spermidine and 100 mM putrescine. With a further increase in polyamines concentration the effect of aggregation acceleration decreased, thus, the modulation of the aggregation rate by polyamines was shown. A comparison of the aggregation kinetics and hydrodynamic radii growth data registered by dynamic light scattering with the data obtained by asymmetric flow field-flow fractionation and analytical ultracentrifugation allowed us to describe the early stages of aggregation and formation of initial α-lactalbumin clusters. Our results provide a deeper insight into the mechanism of amorphous aggregation of α-lactalbumin and polyamines action on protein aggregation and protein-protein interaction in general.

Keywords:  Polyamines; Protein aggregation; Putrescine; Spermidine; α-lactalbumin

DOI:  https://doi.org/10.1016/j.biochi.2024.07.011
Structure. 2024 Jul 12. pii: S0969-2126(24)00236-3. [Epub ahead of print]

Intracellular tau fragment droplets serve as seeds for tau fibrils.

Yoshiyuki Soeda, Hideaki Yoshimura, Hiroko Bannai, Riki Koike, Isshin Shiiba, Akihiko Takashima.

  Intracellular tau aggregation requires a local protein concentration increase, referred to as "droplets". However, the cellular mechanism for droplet formation is poorly understood. Here, we expressed OptoTau, a P301L mutant tau fused with CRY2olig, a light-sensitive protein that can form homo-oligomers. Under blue light exposure, OptoTau increased tau phosphorylation and was sequestered in aggresomes. Suppressing aggresome formation by nocodazole formed tau granular clusters in the cytoplasm. The granular clusters disappeared by discontinuing blue light exposure or 1,6-hexanediol treatment suggesting that intracellular tau droplet formation requires microtubule collapse. Expressing OptoTau-ΔN, a species of N-terminal cleaved tau observed in the Alzheimer's disease brain, formed 1,6-hexanediol and detergent-resistant tau clusters in the cytoplasm with blue light stimulation. These intracellular stable tau clusters acted as a seed for tau fibrils in vitro. These results suggest that tau droplet formation and N-terminal cleavage are necessary for neurofibrillary tangles formation in neurodegenerative diseases.

Keywords:  CRY2olig; aggregation; aggresomes; fragment; liquid-liquid phase separation; oligomers; optogenetics; seeding activity; tau fibrils; tau protein

DOI:  https://doi.org/10.1016/j.str.2024.06.018
Metabolites. 2024 Jun 22. pii: 352. [Epub ahead of print]14(7):

Interaction between α-Synuclein and Bioactive Lipids: Neurodegeneration, Disease Biomarkers and Emerging Therapies.

Chiara Sanluca, Paolo Spagnolo, Romina Mancinelli, Maria Ilenia De Bartolo, Marina Fava, Mauro Maccarrone, Simone Carotti, Eugenio Gaudio, Alessandro Leuti, Giorgio Vivacqua.

  The present review provides a comprehensive examination of the intricate dynamics between α-synuclein, a protein crucially involved in the pathogenesis of several neurodegenerative diseases, including Parkinson's disease and multiple system atrophy, and endogenously-produced bioactive lipids, which play a pivotal role in neuroinflammation and neurodegeneration. The interaction of α-synuclein with bioactive lipids is emerging as a critical factor in the development and progression of neurodegenerative and neuroinflammatory diseases, offering new insights into disease mechanisms and novel perspectives in the identification of potential biomarkers and therapeutic targets. We delve into the molecular pathways through which α-synuclein interacts with biological membranes and bioactive lipids, influencing the aggregation of α-synuclein and triggering neuroinflammatory responses, highlighting the potential of bioactive lipids as biomarkers for early disease detection and progression monitoring. Moreover, we explore innovative therapeutic strategies aimed at modulating the interaction between α-synuclein and bioactive lipids, including the development of small molecules and nutritional interventions. Finally, the review addresses the significance of the gut-to-brain axis in mediating the effects of bioactive lipids on α-synuclein pathology and discusses the role of altered gut lipid metabolism and microbiota composition in neuroinflammation and neurodegeneration. The present review aims to underscore the potential of targeting α-synuclein-lipid interactions as a multifaceted approach for the detection and treatment of neurodegenerative and neuroinflammatory diseases.

Keywords:  bioactive lipids; gut-to-brain axis; neurodegeneration; neuroinflammation; synucleinopathy; α-Synuclein

DOI:  https://doi.org/10.3390/metabo14070352
Front Mol Neurosci. 2024 ;17 1408159

Copper toxicity and deficiency: the vicious cycle at the core of protein aggregation in ALS.

Jin-Hong Min, Heela Sarlus, Robert A Harris.

  The pathophysiology of ALS involves many signs of a disruption in copper homeostasis, with both excess free levels and functional deficiency likely occurring simultaneously. This is crucial, as many important physiological functions are performed by cuproenzymes. While it is unsurprising that many ALS symptoms are related to signs of copper deficiency, resulting in vascular, antioxidant system and mitochondrial oxidative respiration deficiencies, there are also signs of copper toxicity such as ROS generation and enhanced protein aggregation. We discuss how copper also plays a key role in proteostasis and interacts either directly or indirectly with many of the key aggregate-prone proteins implicated in ALS, such as TDP-43, C9ORF72, SOD1 and FUS as well as the effect of their aggregation on copper homeostasis. We suggest that loss of cuproprotein function is at the core of ALS pathology, a condition that is driven by a combination of unbound copper and ROS that can either initiate and/or accelerate protein aggregation. This could trigger a positive feedback cycle whereby protein aggregates trigger the aggregation of other proteins in a chain reaction that eventually captures elements of the proteostatic mechanisms in place to counteract them. The end result is an abundance of aggregated non-functional cuproproteins and chaperones alongside depleted intracellular copper stores, resulting in a general lack of cuproenzyme function. We then discuss the possible aetiology of ALS and illustrate how strong risk factors including environmental toxins such as BMAA and heavy metals can functionally behave to promote protein aggregation and disturb copper metabolism that likely drives this vicious cycle in sporadic ALS. From this synthesis, we propose restoration of copper balance using copper delivery agents in combination with chaperones/chaperone mimetics, perhaps in conjunction with the neuroprotective amino acid serine, as a promising strategy in the treatment of this incurable disease.

Keywords:  ALS; C9ORF72; SOD1; TDP-43; aggregate; copper; neurodegeneration; protein

DOI:  https://doi.org/10.3389/fnmol.2024.1408159
Brain Commun. 2024 ;6(4): fcae232

Spatial selectivity of ATase inhibition in mouse models of Charcot-Marie-Tooth disease.

Gonzalo Fernandez-Fuente, Mark A Farrugia, Yajing Peng, Andrew Schneider, John Svaren, Luigi Puglielli.

  The endoplasmic reticulum acetylation machinery has emerged as a new branch of the larger endoplasmic reticulum quality control system. It regulates the selection of correctly folded polypeptides as well as reticulophagy-mediated removal of toxic protein aggregates with the former being a particularly important aspect of the proteostatic functions of endoplasmic reticulum acetylation. Essential to this function is the Nε-lysine acetyltransferase activity of acetyltransferase 1 and acetyltransferase 2, which regulates the induction of endoplasmic reticulum-specific autophagy through the acetylation of the autophagy-related protein 9A. Here, we used three mouse models of Charcot-Marie-Tooth disease, peripheral myelin protein 22/Tr-J, C3-peripheral myelin protein 22 and myelin protein zero/ttrr, to study spatial and translational selectivity of endoplasmic reticulum acetyltransferase inhibitors. The results show that inhibition of the endoplasmic reticulum acetyltransferases selectively targets misfolding/pro-aggregating events occurring in the lumen of the organelle. Therefore, they establish acetyltransferase 1 and acetyltransferase 2 as the first proven targets for disease-causing proteotoxic states that initiate within the lumen of the endoplasmic reticulum/secretory pathway.

Keywords:  ATase; Charcot–Marie–Tooth disease; acetylation; endoplasmic reticulum; proteostasis

DOI:  https://doi.org/10.1093/braincomms/fcae232