bims-proned 2023-11-05 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2023‒11‒05
eleven papers selected by
Verena Kohler, Umeå University

Navigating α-Synuclein Aggregation Inhibition: Methods, Mechanisms, and Molecular Targets.
Secondary Protein Aggregates in Neurodegenerative Diseases: Almost the Rule Rather than the Exception.
Myocardial infarction elevates endoplasmic reticulum stress and protein aggregation in heart as well as brain.
Modulation of Alpha-Synuclein Conformational Ensemble and Aggregation Pathways by Dopamine and Related Molecules.
SARS-CoV-2 Spike Protein S1 Domain Accelerates α-Synuclein Phosphorylation and Aggregation in Cellular Models of Synucleinopathy.
Amyloid-beta and tau protein beyond Alzheimer's disease.
Understanding and exploiting the roles of O-GlcNAc in neurodegenerative diseases.
A novel cell-permeable peptide prevents protein sumoylation and supports the mislocalization and aggregation of TDP-43.
Crosstalk between protein misfolding and endoplasmic reticulum stress during ageing and their role in age-related disorders.
The yeast prion protein Sup35 initiates α-synuclein pathology in mouse models of Parkinson's disease.
Alpha-secretase dependent nuclear localization of the amyloid-β precursor protein-binding protein Fe65 promotes DNA repair.

Chem Rec. 2023 Nov 02. e202300282

Navigating α-Synuclein Aggregation Inhibition: Methods, Mechanisms, and Molecular Targets.

Maksym Galkin, Anastasiia Priss, Yevhenii Kyriukha, Volodymyr Shvadchak.

  Parkinson's disease is a yet incurable, age-related neurodegenerative disorder characterized by the aggregation of small neuronal protein α-synuclein into amyloid fibrils. Inhibition of this process is a prospective strategy for developing a disease-modifying treatment. We overview here small molecule, peptide, and protein inhibitors of α-synuclein fibrillization reported to date. Special attention was paid to the specificity of inhibitors and critical analysis of their action mechanisms. Namely, the importance of oxidation of polyphenols and cross-linking of α-synuclein into inhibitory dimers was highlighted. We also compared strategies of targeting monomeric, oligomeric, and fibrillar α-synuclein species, thoroughly discussed the strong and weak sides of different approaches to testing the inhibitors.

Keywords:  Parkinson's disease; alpha-synuclein; amyloid; inhibitor; protein misfolding

DOI:  https://doi.org/10.1002/tcr.202300282
Front Biosci (Landmark Ed). 2023 Oct 20. 28(10): 255

Secondary Protein Aggregates in Neurodegenerative Diseases: Almost the Rule Rather than the Exception.

Fabio Moda, Arianna Ciullini, Ilaria Linda Dellarole, Annalisa Lombardo, Nicole Campanella, Giuseppe Bufano, Federico Angelo Cazzaniga, Giorgio Giaccone.

  The presence of protein aggregates is a hallmark of many neurodegenerative diseases, including Parkinson's disease (PD), Alzheimer's disease (AD), and frontotemporal lobar degeneration (FTLD). Traditionally, each disease has been associated with the aggregation of specific proteins, which serve as disease-specific biomarkers. For example, aggregates of α-synuclein (α-syn) are found in α-synucleinopathies such as PD, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Similarly, AD is characterized by aggregates of amyloid-beta (Aβ) and tau proteins. However, it has been observed that these protein aggregates can also occur in other neurodegenerative diseases, contributing to disease progression. For instance, α-syn aggregates have been detected in AD, Down syndrome, Huntington's disease, prion diseases, and various forms of FTLD. Similarly, Aβ aggregates have been found in conditions like DLB and PD. Tau aggregates, in addition to being present in primary tauopathies, have been identified in prion diseases, α-synucleinopathies, and cognitively healthy aged subjects. Finally, aggregates of TDP-43, typically associated with FTLD and amyotrophic lateral sclerosis (ALS), have been observed in AD, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), MSA, DLB, and other neurodegenerative diseases. These findings highlight the complexity of protein aggregation in neurodegeneration and suggest potential interactions and common mechanisms underlying different diseases. A deeper understating of this complex scenario may eventually lead to the identification of a better elucidation of the pathogenetic mechanisms of these devastating conditions and hopefully new therapeutic stragegies.

Keywords:  TDP-43 proteinopathies; alpha-synucleinopathies; biomarker; neurodegeneration; neuropathology; protein aggregation; tautopathies

DOI:  https://doi.org/10.31083/j.fbl2810255
Mol Cell Biochem. 2023 Nov 03.

Myocardial infarction elevates endoplasmic reticulum stress and protein aggregation in heart as well as brain.

Nirjal Mainali, Xiao Li, Xianwei Wang, Meenakshisundaram Balasubramaniam, Akshatha Ganne, Rajshekhar Kore, Robert J Shmookler Reis, Jawahar L Mehta, Srinivas Ayyadevara.

  Cardiovascular diseases, including myocardial infarction (MI), constitute the leading cause of morbidity and mortality worldwide. Protein-aggregate deposition is a hallmark of aging and neurodegeneration. Our previous study reported that aggregation is strikingly elevated in hearts of hypertensive and aged mice; however, no prior study has addressed MI effects on aggregation in heart or brain. Here, we present novel data on heart and brain aggregation in mice following experimental MI, induced by left coronary artery (LCA) ligation. Infarcted and peri-infarcted heart tissue, and whole cerebra, were isolated from mice at sacrifice, 7 days following LCA ligation. Sham-MI mice (identical surgery without ligation) served as controls. We purified detergent-insoluble aggregates from these tissues, and quantified key protein constituents by high-resolution mass spectrometry (LC-MS/MS). Infarct heart tissue had 2.5- to 10-fold more aggregates than non-infarct or sham-MI heart tissue (each P = 0.001). Protein constituents from MI cerebral aggregates overlapped substantially with those from human Alzheimer's disease brain. Prior injection of mice with mesenchymal stem cell (MSC) exosomes, shown to limit infarct size after LCA ligation, reduced cardiac aggregation ~ 60%, and attenuated markers of endoplasmic reticulum (ER) stress in heart and brain (GRP78, ATF6, P-PERK) by 50-75%. MI also elevated aggregate constituents enriched in Alzheimer's disease (AD) aggregates, such as proteasomal subunits, heat-shock proteins, complement C3, clusterin/ApoJ, and other apolipoproteins. These data provide novel evidence that aggregation is elevated in mouse hearts and brains after myocardial ischemia, leading to cognitive impairment resembling AD, but can be attenuated by exosomes or drug (CDN1163) interventions that oppose ER stress.

Keywords:  Aging; Alzheimer’s disease; Endoplasmic reticulum stress (ER stress); Exosomes; Hypoxia; Myocardial infarction (MI); Protein aggregation

DOI:  https://doi.org/10.1007/s11010-023-04856-3
Front Biosci (Landmark Ed). 2023 Oct 26. 28(10): 266

Modulation of Alpha-Synuclein Conformational Ensemble and Aggregation Pathways by Dopamine and Related Molecules.

Antonino Natalello, Stefania Brocca, Erika Ponzini, Carlo Santambrogio, Rita Grandori.

  Dopaminergic neurons are constantly threatened by the thin boundaries between functional α-synuclein (AS) structural disorder and pathogenic aggregation, and between dopamine (DA) neurotransmitter activity and accumulation of cytotoxic by-products. The possibilities of developing drugs for Parkinson's disease (PD) depend on our understanding of the molecular mechanisms that cause or accompany the pathological structural changes in AS. This review focuses on the three interconnected aspects of AS conformational transitions, its aggregation pathways and ligand binding. Specifically, the interactions of AS with DA, DA metabolites, DA analogs and DA agonists are considered. Recent advances in the field are discussed with reference to the structural properties of AS and the methodologies employed. Although several issues are still object of debate, salient structural features of the protein, the aggregates and the ligands can be identified, in the hope of fueling experimental and computational approaches to the discovery of novel disease-modifying agents.

Keywords:  catecholamines; intrinsically disordered proteins; ligand binding; oxidative stress; synucleinopathies

DOI:  https://doi.org/10.31083/j.fbl2810266
Mol Neurobiol. 2023 Oct 28.

SARS-CoV-2 Spike Protein S1 Domain Accelerates α-Synuclein Phosphorylation and Aggregation in Cellular Models of Synucleinopathy.

Jiannan Wang, Lijun Dai, Min Deng, Tingting Xiao, Zhaohui Zhang, Zhentao Zhang.

  The 2019 novel coronavirus disease (COVID-19) is an infectious disease that began to spread globally since 2019. Some COVID-19 patients have neurological complications, such as olfactory disorders and movement disorders, which coincide with the symptoms of Parkinson's disease (PD). Increasing imaging and autopsy evidence supports that the density of dopaminergic neurons in the nigrostriatal pathway is damaged in some COVID-19 patients. However, the underlying mechanism that causes PD-like symptoms remains unclear. PD is an age-related neurodegenerative disease with Lewy bodies (LBs) as its histopathologic feature. The main component of LBs is abnormally aggregated α-synuclein (α-syn). The prion-like propagation of α-syn aggregates plays a key role in the onset and progression of PD. The spike protein (S protein) of SARS-CoV-2 is a heparin-binding protein that mediates the entry of the virus into host cells. Here we found that the S1 domain interacts with α-syn and promotes α-syn aggregation. The S1 domain induces mitochondrial dysfunction, oxidative stress, and cytotoxicity. The S1-seeded α-syn fibrils show enhanced seeding activity and induce synaptic damage and cytotoxicity. Thus, the S1 domain of SARS-CoV-2 promotes the aggregation of α-syn in the cellular model of synucleinopathy and may contribute to the pathogenesis of PD.

Keywords:  COVID-19; Cytotoxicity; Lewy body; Parkinson’s disease; Virus protein

DOI:  https://doi.org/10.1007/s12035-023-03726-9
Neural Regen Res. 2024 Jun 01. 19(6): 1262-1276

Amyloid-beta and tau protein beyond Alzheimer's disease.

Morteza Abyadeh, Vivek Gupta, Joao A Paulo, Arezoo Gohari Mahmoudabad, Sina Shadfar, Shahab Mirshahvaladi, Veer Gupta, Christine T O Nguyen, David I Finkelstein, Yuyi You, Paul A Haynes, Ghasem H Salekdeh, Stuart L Graham, Mehdi Mirzaei.

ABSTRACT: The aggregation of amyloid-beta peptide and tau protein dysregulation are implicated to play key roles in Alzheimer's disease pathogenesis and are considered the main pathological hallmarks of this devastating disease. Physiologically, these two proteins are produced and expressed within the normal human body. However, under pathological conditions, abnormal expression, post-translational modifications, conformational changes, and truncation can make these proteins prone to aggregation, triggering specific disease-related cascades. Recent studies have indicated associations between aberrant behavior of amyloid-beta and tau proteins and various neurological diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, as well as retinal neurodegenerative diseases like Glaucoma and age-related macular degeneration. Additionally, these proteins have been linked to cardiovascular disease, cancer, traumatic brain injury, and diabetes, which are all leading causes of morbidity and mortality. In this comprehensive review, we provide an overview of the connections between amyloid-beta and tau proteins and a spectrum of disorders.

DOI: https://doi.org/10.4103/1673-5374.386406
J Biol Chem. 2023 Oct 31. pii: S0021-9258(23)02439-0. [Epub ahead of print] 105411

Understanding and exploiting the roles of O-GlcNAc in neurodegenerative diseases.

Matthew R Pratt, David J Vocadlo.

  O-GlcNAc is a common modification found on nuclear and cytoplasmic proteins. Determining the catalytic mechanism of the enzyme O-GlcNAcase (OGA), which removes O-GlcNAc from proteins, enabled the creation of potent and selective inhibitors of this regulatory enzyme. Such inhibitors have served as important tools in helping to uncover the cellular and organismal physiological roles of this modification. Additionally, OGA inhibitors have been important for defining the augmentation of O-GlcNAc as a promising disease-modifying approach to combat several neurodegenerative diseases including both Alzheimer's and Parkinson's Disease. These studies have led to development and optimization of OGA inhibitors for clinical application. These compounds have been shown to be well tolerated in early clinical studies and are steadily advancing into the clinic. Despite these advances, the mechanisms by which O-GlcNAc protects against these various types of neurodegeneration are a topic of continuing interest since improved insight may enable the creation of more targeted strategies to modulate O-GlcNAc for therapeutic benefit. Relevant pathways on which O-GlcNAc has been found to exert beneficial effects include autophagy, necroptosis, and processing of the amyloid precursor protein. More recently, the development and application of chemical methods enabling the synthesis of homogenous proteins have clarified the biochemical effects of O-GlcNAc on protein aggregation and uncovered new roles for O-GlcNAc in heat shock response. Here, we discuss the features of O-GlcNAc in neurodegenerative diseases, the application of inhibitors to identify the roles of this modification, and the biochemical effects of O-GlcNAc on proteins and pathways associated with neurodegeneration.

Keywords:  Alzheimer disease; Neurodegeneration; O-GlcNAc; clinical development; enzyme inhibitors; protein synthesis; synuclein; tau

DOI:  https://doi.org/10.1016/j.jbc.2023.105411
Neurobiol Dis. 2023 Oct 31. pii: S0969-9961(23)00358-3. [Epub ahead of print] 106342

A novel cell-permeable peptide prevents protein sumoylation and supports the mislocalization and aggregation of TDP-43.

R Marino, L Buccarello, K Hassanzadeh, K Akhtari, S Palaniappan, M Corbo, M Feligioni.

  SUMOylation is a post-translational modification (PTM) that exerts a regulatory role in different cellular processes, including protein localization, aggregation, and biological activities. It consists of the dynamic formation of covalent isopeptide bonds between a family member of the Small Ubiquitin Like Modifiers (SUMOs) and the target proteins. Interestingly, it is a cellular mechanism implicated in several neurodegenerative pathologies and potentially it could become a new therapeutic target; however, there are very few pharmacological tools to modulate the SUMOylation process. In this study, we have designed and tested the activity of a novel small cell-permeable peptide, COV-1, in a neuroblastoma cell line that specifically prevents protein SUMOylation. COV-1 inhibits UBC9-protein target interaction and efficiently decreases global SUMO-1ylation. Moreover, it can perturb RanGAP-1 perinuclear localization by inducing the downregulation of UBC9. In parallel, we found that COV-1 causes an increase in the ubiquitin degradation system up to its engulfment while enhancing the autophagic flux. Surprisingly, COV-1 modifies protein aggregation, and specifically it mislocalizes TDP-43 within cells, inducing its aggregation and co-localization with SUMO-1. These data suggest that COV-1 could be taken into future consideration as an interesting pharmacological tool to study the cellular cascade effects of SUMOylation prevention.

Keywords:  Aggregation; Autophagy; Cell-permeable peptides; Mislocalization; Protein target; RanGAP-1; SUMOylation; TDP43; UBC9; Ubiquitination

DOI:  https://doi.org/10.1016/j.nbd.2023.106342
Biochimie. 2023 Oct 31. pii: S0300-9084(23)00290-0. [Epub ahead of print]

Crosstalk between protein misfolding and endoplasmic reticulum stress during ageing and their role in age-related disorders.

Manisekaran Hemagirri, Yeng Chen, Subash C B Gopinath, Sumaira Sahreen, Mohd Adnan, Sreenivasan Sasidharan.

  Maintaining the proteome is crucial to retaining cell functionality and response to multiple intrinsic and extrinsic stressors. Protein misfolding increased the endoplasmic reticulum (ER) stress and activated the adaptive unfolded protein response (UPR) to restore cell homeostasis. Apoptosis occurs when ER stress is prolonged or the adaptive response fails. In healthy young cells, the ratio of protein folding machinery to quantities of misfolded proteins is balanced under normal circumstances. However, the age-related deterioration of the complex systems for handling protein misfolding is accompanied by ageing-related disruption of protein homeostasis, which results in the build-up of misfolded and aggregated proteins. This ultimately results in decreased cell viability and forms the basis of common age-related diseases called protein misfolding diseases. Proteins or protein fragments convert from their ordinarily soluble forms to insoluble fibrils or plaques in many of these disorders, which build up in various organs such as the liver, brain, or spleen. Alzheimer's, Parkinson's, type II diabetes, and cancer are diseases in this group commonly manifest in later life. Thus, protein misfolding and its prevention by chaperones and different degradation paths are becoming understood from molecular perspectives. Proteodynamics information will likely affect future interventional techniques to combat cellular stress and support healthy ageing by avoiding and treating protein conformational disorders. This review provides an overview of the diverse proteostasis machinery, protein misfolding, and ER stress involvement, which activates the UPR sensors. Here, we will discuss the crosstalk between protein misfolding and ER stress and their role in developing age-related diseases.

Keywords:  Age-related diseases; Ageing; Endoplasmic reticulum stress response; Protein misfolding; Proteostasis; Unfolded protein response

DOI:  https://doi.org/10.1016/j.biochi.2023.10.019
Sci Adv. 2023 11 03. 9(44): eadj1092

The yeast prion protein Sup35 initiates α-synuclein pathology in mouse models of Parkinson's disease.

Lanxia Meng, Congcong Liu, Yiming Li, Guiqin Chen, Min Xiong, Ting Yu, Lina Pan, Xingyu Zhang, Lingyan Zhou, Tao Guo, Xin Yuan, Chaoyang Liu, Zhaohui Zhang, Zhentao Zhang.

Parkinson's disease (PD) is characterized by the pathologic aggregation and prion-like propagation of α-synuclein (α-syn). Emerging evidence shows that fungal infections increase the incidence of PD. However, the molecular mechanisms by which fungi promote the onset of PD are poorly understood. Here, we show that nasal infection with Saccharomyces cerevisiae (S. cerevisiae) in α-syn A53T transgenic mice accelerates the aggregation of α-syn. Furthermore, we found that Sup35, a prion protein from S. cerevisiae, is the key factor initiating α-syn pathology induced by S. cerevisiae. Sup35 interacts with α-syn and accelerates its aggregation in vitro. Notably, injection of Sup35 fibrils into the striatum of wild-type mice led to α-syn pathology and PD-like motor impairment. The Sup35-seeded α-syn fibrils showed enhanced seeding activity and neurotoxicity compared with pure α-syn fibrils in vitro and in vivo. Together, these observations indicate that the yeast prion protein Sup35 initiates α-syn pathology in PD.

DOI: https://doi.org/10.1126/sciadv.adj1092
Mol Cell Neurosci. 2023 Oct 31. pii: S1044-7431(23)00097-0. [Epub ahead of print] 103903

Alpha-secretase dependent nuclear localization of the amyloid-β precursor protein-binding protein Fe65 promotes DNA repair.

Rebecca S Revol, Niina A Koistinen, Preeti K Menon, Almudena Chicote-Gonzàlez, Kerstin Iverfeldt, Anna-Lena Ström.

  Fe65 is a brain enriched adaptor protein involved in various cellular processes, including actin cytoskeleton regulation, DNA repair and transcription. A well-studied interacting partner of Fe65 is the transmembrane amyloid-β precursor protein (APP), which can undergo regulated intramembrane proteolysis (RIP). Following β- and γ-secretase-mediated RIP, the released APP intracellular domain (AICD) together with Fe65 can translocate to the nucleus and regulate transcription. In this study, we investigated if Fe65 nuclear localization can also be regulated by different α-secretases, also known to participate in RIP of APP and other transmembrane proteins. We found that in both Phorbol 12-myristate 13-acetate and all-trans retinoic acid differentiated neuroblastoma cells a strong negative impact on Fe65 nuclear localization, equal to the effect observed upon γ-secretase inhibition, could be detected following inhibition of all three (ADAM9, ADAM10 and ADAM17) α-secretases. Moreover, using the comet assay and analysis of Fe65 dependent DNA repair associated posttranslational modifications of histones, we could show that inhibition of α-secretase-mediated Fe65 nuclear translocation resulted in impaired capacity of the cells to repair DNA damage. Taken together this suggests that α-secretase processing of APP and/or other Fe65 interacting transmembrane proteins play an important role in regulating Fe65 nuclear translocation and DNA repair.

Keywords:  Alpha-secretase; Alzheimer's disease; Amyloid-β precursor protein; DNA repair; Fe65

DOI:  https://doi.org/10.1016/j.mcn.2023.103903