bims-proned Biomed News
on Proteostasis in neurodegeneration
Issue of 2024‒01‒14
fourteen papers selected by
Verena Kohler, Umeå University

  1. Chem Commun (Camb). 2024 Jan 11.
      Biomolecule misfolding and aggregation play a major role in human disease, spanning from neurodegeneration to cancer. Inhibition of these processes is of considerable interest, and due to the multifactorial nature of these diseases, the development of drugs that act on multiple pathways simultaneously is a promising approach. This Feature Article focuses on the development of multifunctional molecules designed to inhibit the misfolding and aggregation of the amyloid-β (Aβ) peptide in Alzheimer's disease (AD), and the mutant p53 protein in cancer. While for the former, the goal is to accelerate the removal of the Aβ peptide and associated aggregates, for the latter, the goal is reactivation via stabilization of the active folded form of mutant p53 protein and/or aggregation inhibition. Due to the similar aggregation pathway of the Aβ peptide and mutant p53 protein, a common therapeutic approach may be applicable.
  2. Cell Commun Signal. 2024 Jan 12. 22(1): 31
      The intracellular deposition and intercellular transmission of α-synuclein (α-syn) are shared pathological characteristics among neurodegenerative disorders collectively known as α-synucleinopathies, including Parkinson's disease (PD). Although the precise triggers of α-synucleinopathies remain unclear, recent findings indicate that disruption of microglial homeostasis contributes to the pathogenesis of PD. Microglia play a crucial role in maintaining optimal neuronal function by ensuring a homeostatic environment, but this function is disrupted during the progression of α-syn pathology. The involvement of microglia in the accumulation, uptake, and clearance of aggregated proteins is critical for managing disease spread and progression caused by α-syn pathology. This review summarizes current knowledge on the interrelationships between microglia and α-synucleinopathies, focusing on the remarkable ability of microglia to recognize and internalize extracellular α-syn through diverse pathways. Microglia process α-syn intracellularly and intercellularly to facilitate the α-syn neuronal aggregation and cell-to-cell propagation. The conformational state of α-synuclein distinctly influences microglial inflammation, which can affect peripheral immune cells such as macrophages and lymphocytes and may regulate the pathogenesis of α-synucleinopathies. We also discuss ongoing research efforts to identify potential therapeutic approaches targeting both α-syn accumulation and inflammation in PD. Video Abstract.
    Keywords:  Central nervous system; Inflammation; Microglia; Parkinson's disease; α-synuclein
  3. Biomed Pharmacother. 2024 Jan 05. pii: S0753-3322(23)01869-3. [Epub ahead of print]171 116071
      Sphingolipids (SPLs) represent a highly diverse and structurally complex lipid class. The discussion of SPL metabolism-related issues is of importance in understanding the neuropathological progression of Alzheimer's disease (AD). AD is characterized by the accumulation of extracellular deposits of the amyloid β-peptide (Aβ) and intraneuronal aggregates of the microtubule-associated protein tau. Critical roles of Aβ oligomer deposited and ganglioside GM1 could be formed as "seed" from insoluble GAβ polymer in initiating the pathogenic process, while tau might also mediate SPLs and their toxicity. The interaction between ceramide and α-Synuclein (α-Syn) accelerates the aggregation of ferroptosis and exacerbates the pathogenesis of AD. For instance, reducing the levels of SPLs can mitigate α-Syn accumulation and inhibit AD progression. Meanwhile, loss of SPLs may inhibit the expression of APOE4 and confer protection against AD, while the loss of APOE4 expression also disrupts SPLs homeostasis. Moreover, the heightened activation of sphingomyelinase promotes the ferroptosis signaling pathway, leading to exacerbated AD symptoms. Ferroptosis plays a vital role in the pathological progression of AD by influencing Aβ, tau, APOE, and α-Syn. Conversely, the development of AD also exacerbates the manifestation of ferroptosis and SPLs. We are compiling the emerging techniques (Derivatization and IM-MS) of sphingolipidomics, to overcome the challenges of AD diagnosis and treatment. In this review, we examined the intricate neuro-mechanistic interactions between SPLs and Aβ, tau, α-Syn, APOE, and ferroptosis, mediating the onset of AD. Furthermore, our findings highlight the potential of targeting SPLs as underexplored avenue for devising innovative therapeutic strategies against AD.
    Keywords:  Alzheimer's disease; Aβ; Ceramide; Ferroptosis; Ganglioside GM1; Sphingolipids (SPLs)
  4. ACS Chem Neurosci. 2024 Jan 09.
      The molecular determinants of amyloid protein misfolding and aggregation are key for the development of therapeutic interventions in neurodegenerative disease. Although small synthetic molecules, bifunctional molecules, and natural products offer a potentially advantageous approach to therapeutics to remodel aggregation, their evaluation requires new platforms that are informed at the molecular level. To that end, we chose pulsed hydrogen/deuterium exchange mass spectrometry (HDX-MS) to discern the phenomena of aggregation modulation for a model system of alpha synuclein (αS) and resveratrol, an antiamyloid compound. We invoked, as a complement to HDX, advanced kinetic modeling described here to illuminate the details of aggregation and to determine the number of oligomeric populations by kinetically fitting the experimental data under conditions of limited proteolysis. The misfolding of αS is most evident within and nearby the nonamyloid-β component region, and resveratrol significantly remodels that aggregation. HDX distinguishes readily a less solvent-accessible, more structured oligomer that coexists with a solvent-accessible, more disordered oligomer during aggregation. A view of the misfolding emerges from time-dependent changes in the fractional species across the protein with or without resveratrol, while details were determined through kinetic modeling of the protected species. A detailed picture of the inhibitory action of resveratrol with time and regional specificity emerges, a picture that can be obtained for other inhibitors and amyloid proteins. Moreover, the model reveals that new states of aggregation are sampled, providing new insights on amyloid formation. The findings were corroborated by circular dichroism and transmission electron microscopy.
    Keywords:  amyloid formation; kinetic modeling of aggregation; limited proteolysis; modulator of alpha-synuclein; protein aggregation; pulsed hydrogen/deuterium exchange; resveratrol
  5. Nutrients. 2023 Dec 26. pii: 85. [Epub ahead of print]16(1):
      Parkinson's disease (PD) is the second most common neurological disorder, pathologically characterized by loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) as well as the formation of Lewy bodies composed mainly of α-synuclein (α-syn) aggregates. It has been documented that abnormal aggregation of α-syn is one of the major causes of developing PD. In the current study, administration of ellagic acid (EA), a polyphenolic compound (10 mg/kg bodyweight), significantly decreased α-syn spreading and preserved dopaminergic neurons in a male C57BL/6 mouse model of PD. Moreover, EA altered the autophagic flux, suggesting the involvement of a restorative mechanism meditated by EA treatment. Our data support that EA could play a major role in the clearing of toxic α-syn from spreading, in addition to the canonical antioxidative role, and thus preventing dopaminergic neuronal death.
    Keywords:  PD mouse model; Parkinson’s disease; autophagy; ellagic acid; α-synuclein
  6. ACS Chem Neurosci. 2024 Jan 11.
      Alzheimer's disease (AD) is a devastating, progressive neurodegenerative disease affecting the elderly in the world. The pathological hallmark senile plaques are mainly composed of amyloid-β (Aβ), in which the main isoforms are Aβ40 and Aβ42. Aβ is prone to aggregate and ultimately forms amyloid fibrils in the brains of AD patients. Factors that alter the Aβ aggregation process have been considered to be potential targets for treatments of AD. Modifier of aggregation 4 (MOAG-4)/small EDRK-rich factor (SERF) was previously selected from a chemical mutagenesis screen and identified as an amyloid modifier that promotes amyloid aggregation for α-synuclein, huntingtin, and Aβ40. The interaction and effect of yeast ScSERF on Aβ40 were previously described. Here, we examined the human SERF1a effect on Aβ40 and Aβ42 fibrillization by the Thioflavin T assay and found that SERF1a accelerated Aβ fibrillization in a dose-dependent manner without changing the fibril amount and without incorporation. By Fourier transform infrared spectroscopy (FTIR) and transmission electron microscopy (TEM), we found that SERF1a altered the secondary structures and the morphology of Aβ fibrils. The electrospray ionization mass spectrometry (ESI-MS) and analytical ultracentrifugation (AUC) results showed that SERF1a binds to Aβ in a 1:1 stoichiometry. Moreover, the NMR study showed that SERF1a interacts with Aβ via its N-terminal region. Cytotoxicity assay demonstrated that SERF1a enhanced toxicity of Aβ intermediates, and the effect can be rescued by SERF1a antibody. Overall, our study provides the underlying molecular mechanism for the SERF1a effect on Aβ fibrillization and facilitates the therapeutic development of AD.
    Keywords:  Alzheimer’s disease; SERF1a; aggregation; amyloid-β (Aβ); protein–protein interaction; toxicity
  7. Biophys Chem. 2024 Jan 07. pii: S0301-4622(24)00003-6. [Epub ahead of print]306 107174
      The progressive aggregation of misfolded proteins is the underlying molecular cause of numerous pathologies including Parkinson's disease and injection and transthyretin amyloidosis. A growing body of evidence indicates that protein deposits detected in organs and tissues of patients diagnosed with such pathologies contain fragments of lipid membranes. In vitro experiments also showed that lipid membranes could strongly change the aggregation rate of amyloidogenic proteins, as well as alter the secondary structure and toxicity of oligomers and fibrils formed in their presence. In this review, the effect of large unilamellar vesicles (LUVs) composed of zwitterionic and anionic phospholipids on the aggregation rate of insulin, lysozyme, transthyretin (TTR) and α- synuclein (α-syn) will be discussed. The manuscript will also critically review the most recent findings on the lipid-induced changes in the secondary structure of protein oligomers and fibrils, as well as reveal the extent to which lipids could alter the toxicity of protein aggregates formed in their presence.
    Keywords:  Amyloid fibrils; LUVs; Neurodegeneration; Oligomers; Toxicity
  8. Proc Natl Acad Sci U S A. 2024 Jan 16. 121(3): e2312031121
      The quantification and characterization of aggregated α-synuclein in clinical samples offer immense potential toward diagnosing, treating, and better understanding neurodegenerative synucleinopathies. Here, we developed digital seed amplification assays to detect single α-synuclein aggregates by partitioning the reaction into microcompartments. Using pre-formed α-synuclein fibrils as reaction seeds, we measured aggregate concentrations as low as 4 pg/mL. To improve our sensitivity, we captured aggregates on antibody-coated magnetic beads before running the amplification reaction. By first characterizing the pre-formed fibrils with transmission electron microscopy and size exclusion chromatography, we determined the specific aggregates targeted by each assay platform. Using brain tissue and cerebrospinal fluid samples collected from patients with Parkinson's Disease and multiple system atrophy, we demonstrated that the assay can detect endogenous pathological α-synuclein aggregates. Furthermore, as another application for these assays, we studied the inhibition of α-synuclein aggregation in the presence of small-molecule inhibitors and used a custom image analysis pipeline to quantify changes in aggregate growth and filament morphology.
    Keywords:  Parkinson’s disease (PD); digital assay; protein aggregation; seed amplification assay (SAA); α-synuclein
  9. Exp Mol Med. 2024 Jan 11.
      Arrestins are multifunctional proteins that regulate G-protein-coupled receptor (GPCR) desensitization, signaling, and internalization. The arrestin family consists of four subtypes: visual arrestin1, β-arrestin1, β-arrestin2, and visual arrestin-4. Recent studies have revealed the multifunctional roles of β-arrestins beyond GPCR signaling, including scaffolding and adapter functions, and physically interacting with non-GPCR receptors. Increasing evidence suggests that β-arrestins are involved in the pathogenesis of a variety of neurodegenerative diseases, including Alzheimer's disease (AD), frontotemporal dementia (FTD), and Parkinson's disease (PD). β-arrestins physically interact with γ-secretase, leading to increased production and accumulation of amyloid-beta in AD. Furthermore, β-arrestin oligomers inhibit the autophagy cargo receptor p62/SQSTM1, resulting in tau accumulation and aggregation in FTD. In PD, β-arrestins are upregulated in postmortem brain tissue and an MPTP model, and the β2AR regulates SNCA gene expression. In this review, we aim to provide an overview of β-arrestin1 and β-arrestin2, and describe their physiological functions and roles in neurodegenerative diseases. The multifaceted roles of β-arrestins and their involvement in neurodegenerative diseases suggest that they may serve as promising therapeutic targets.
  10. Front Chem. 2023 ;11 1343118
      Alzheimer's disease and Parkinson's disease are the two most common neurodegenerative diseases globally. These neurodegenerative diseases have characteristic late-stage symptoms allowing for differential diagnosis; however, they both share the presence of misfolded protein aggregates which appear years before clinical manifestation. Historically, research has focused on the detection of higher-ordered aggregates (or amyloids); however, recent evidence has shown that the oligomeric state of these protein aggregates plays a greater role in disease pathology, resulting in increased efforts to detect oligomers to aid in disease diagnosis. In this review, we summarize some of the exciting new developments towards the development of fluorescent probes that can detect oligomeric aggregates of amyloidogenic proteins present in Alzheimer's and Parkinson's disease patients.
    Keywords:  fluorescence; neurodegenerative diseases; oligomers; probes; proteins
  11. Int J Mol Sci. 2023 Dec 26. pii: 360. [Epub ahead of print]25(1):
      Parkinson's disease (PD) is a complex neurodegenerative disease characterized by the progressive loss of dopaminergic neurons in the substantia nigra and the widespread accumulation of alpha-synuclein (αSyn) protein aggregates. αSyn aggregation disrupts critical cellular processes, including synaptic function, mitochondrial integrity, and proteostasis, which culminate in neuronal cell death. Importantly, αSyn pathology extends beyond neurons-it also encompasses spreading throughout the neuronal environment and internalization by microglia and astrocytes. Once internalized, glia can act as neuroprotective scavengers, which limit the spread of αSyn. However, they can also become reactive, thereby contributing to neuroinflammation and the progression of PD. Recent advances in αSyn research have enabled the molecular diagnosis of PD and accelerated the development of targeted therapies. Nevertheless, despite more than two decades of research, the cellular function, aggregation mechanisms, and induction of cellular damage by αSyn remain incompletely understood. Unraveling the interplay between αSyn, neurons, and glia may provide insights into disease initiation and progression, which may bring us closer to exploring new effective therapeutic strategies. Herein, we provide an overview of recent studies emphasizing the multifaceted nature of αSyn and its impact on both neuron and glial cell damage.
    Keywords:  Lewy bodies; Parkinson’s disease; aggregation; glial cells; neurodegeneration; neuroinflammation; neurons; seeding; α-synuclein
  12. Int J Mol Sci. 2023 Dec 29. pii: 481. [Epub ahead of print]25(1):
      Up-regulated Gene clone 7 (URG7) is a protein localized in the endoplasmic reticulum (ER) and overexpressed in liver cells upon hepatitis B virus (HBV) infection. Its activity has been related to the attenuation of ER stress resulting from HBV infection, promoting protein folding and ubiquitination and reducing cell apoptosis overall. While the antiapoptotic activity of URG7 in HBV-infected cells may have negative implications, this effect could be exploited positively in the field of proteinopathies, such as neurodegenerative diseases. In this work, we aimed to verify the possible contribution of URG7 as a reliever of cellular proteostasis alterations in a neuronal in vitro system. Following tunicamycin-induced ER stress, URG7 was shown to modulate different markers of the unfolded protein response (UPR) in favor of cell survival, mitigating ER stress and activating autophagy. Furthermore, URG7 promoted ubiquitination, and determined a reduction in protein aggregation, calcium release from the ER and intracellular ROS content, confirming its pro-survival activity. Therefore, in light of the results reported in this work, we hypothesize that URG7 offers activity as an ER stress reliever in a neuronal in vitro model, and we paved the way for a new approach in the treatment of neurodegenerative diseases.
    Keywords:  PI3K/AKT pathway; apoptosis; autophagy; endoplasmic reticulum (ER) stress; neurodegeneration; protein misfolding; tunicamycin; unfolded protein response (UPR)
  13. Nat Commun. 2024 Jan 12. 15(1): 486
      The transactive response DNA-binding protein-43 (TDP-43) is a multi-facet protein involved in phase separation, RNA-binding, and alternative splicing. In the context of neurodegenerative diseases, abnormal aggregation of TDP-43 has been linked to amyotrophic lateral sclerosis and frontotemporal lobar degeneration through the aggregation of its C-terminal domain. Here, we report a cryo-electron microscopy (cryo-EM)-based structural characterization of TDP-43 fibrils obtained from the full-length protein. We find that the fibrils are polymorphic and contain three different amyloid structures. The structures differ in the number and relative orientation of the protofilaments, although they share a similar fold containing an amyloid key motif. The observed fibril structures differ from previously described conformations of TDP-43 fibrils and help to better understand the structural landscape of the amyloid fibril structures derived from this protein.
  14. Cells. 2023 Dec 20. pii: 8. [Epub ahead of print]13(1):
      Small ubiquitin-related modifiers (SUMOs) function as post-translational protein modifications and regulate nearly every aspect of cellular function. While a single ubiquitin protein is expressed across eukaryotic organisms, multiple SUMO paralogues with distinct biomolecular properties have been identified in plants and vertebrates. Five SUMO paralogues have been characterized in humans, with SUMO1, SUMO2 and SUMO3 being the best studied. SUMO2 and SUMO3 share 97% protein sequence homology (and are thus referred to as SUMO2/3) but only 47% homology with SUMO1. To date, thousands of putative sumoylation substrates have been identified thanks to advanced proteomic techniques, but the identification of SUMO1- and SUMO2/3-specific modifications and their unique functions in physiology and pathology are not well understood. The SUMO2/3 paralogues play an important role in proteostasis, converging with ubiquitylation to mediate protein degradation. This function is achieved primarily through SUMO-targeted ubiquitin ligases (STUbLs), which preferentially bind and ubiquitylate poly-SUMO2/3 modified proteins. Effects of the SUMO1 paralogue on protein solubility and aggregation independent of STUbLs and proteasomal degradation have also been reported. Consistent with these functions, sumoylation is implicated in multiple human diseases associated with disturbed proteostasis, and a broad range of pathogenic proteins have been identified as SUMO1 and SUMO2/3 substrates. A better understanding of paralogue-specific functions of SUMO1 and SUMO2/3 in cellular protein quality control may therefore provide novel insights into disease pathogenesis and therapeutic innovation. This review summarizes current understandings of the roles of sumoylation in protein quality control and associated diseases, with a focus on the specific effects of SUMO1 and SUMO2/3 paralogues.
    Keywords:  SUMO; cardiovascular disease; cystic fibrosis; neurodegenerative disease; protein quality control; proteostasis