bims-proned 2023-08-27 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2023–08–27
ten papers selected by
Verena Kohler, University of Graz

Elucidation of Secondary Structure and Toxicity of α-Synuclein Oligomers and Fibrils Grown in the Presence of Phosphatidylcholine and Phosphatidylserine.
Inhibition of Protein Aggregation and Endoplasmic Reticulum Stress as a Targeted Therapy for α-Synucleinopathy.
Role of aberrant phase separation in pathological protein aggregation.
Calcineurin stimulation by Cnb1p overproduction mitigates protein aggregation and α-synuclein toxicity in a yeast model of synucleinopathy.
α-Synuclein Aggregation Inhibitory and Antiplasmodial Activity of Constituents from the Australian Tree Eucalyptus cloeziana.
Tuning Hsp104 specificity to selectively detoxify α-synuclein.
Nucleocytoplasmic transport at the crossroads of proteostasis, neurodegeneration and neuroprotection.
Roles of Oxidative Stress in Synaptic Dysfunction and Neuronal Cell Death in Alzheimer's Disease.
Proteostasis plays an important role in demyelinating Charcot Marie Tooth disease.
The Unfolded Protein Response: A Double-Edged Sword for Brain Health.

ACS Chem Neurosci. 2023 Aug 21.

Elucidation of Secondary Structure and Toxicity of α-Synuclein Oligomers and Fibrils Grown in the Presence of Phosphatidylcholine and Phosphatidylserine.

Tianyi Dou, Mikhail Matveyenka, Dmitry Kurouski.

  Abrupt aggregation of α-synuclein (α-Syn) in the midbrain hypothalamus and thalamus is a hallmark of Parkinson's disease (PD), the fastest growing neurodegenerative pathology, projected to strike 12 million people by 2040 worldwide. In this study, we examine the effect of two phospholipids that are present in neuronal membranes, phosphatidylcholine (PC) and phosphatidylserine (PS), on the rate of α-Syn aggregation. We found that PS accelerated α-Syn aggregation, whereas PC strongly inhibited α-Syn aggregation. We also utilized the nano-infrared imaging technique, also known as atomic force microscopy infrared (AFM-IR) spectroscopy, to investigate whether PC and PS only change the rates or also modify the secondary structure of α-Syn aggregates. We found that both phospholipids uniquely altered the secondary structure of α-Syn aggregates present at the lag and growth phase, as well as the late stage of protein aggregation. In addition, compared to the α-Syn aggregates formed in the lipid-free environment, α-Syn:PC and α-Syn:PS aggregates demonstrated higher cellular toxicity to N27 rat neurons. Interestingly, both α-Syn:PC and α-Syn:PS aggregates showed similar levels of oxidative stress, but α-Syn:PC aggregates exhibited a greater degree of mitochondrial dysfunction compared to α-Syn:PS aggregates.

Keywords:  AFM-IR; and phosphatidylserine; cytotoxicity; phosphatidylcholine; protein secondary structure; protein−lipid interactions; α-synuclein aggregation

DOI:  https://doi.org/10.1021/acschemneuro.3c00314
Pharmaceutics. 2023 Jul 30. pii: 2051. [Epub ahead of print]15(8):

Inhibition of Protein Aggregation and Endoplasmic Reticulum Stress as a Targeted Therapy for α-Synucleinopathy.

Natalia Siwecka, Kamil Saramowicz, Grzegorz Galita, Wioletta Rozpędek-Kamińska, Ireneusz Majsterek.

  α-synuclein (α-syn) is an intrinsically disordered protein abundant in the central nervous system. Physiologically, the protein regulates vesicle trafficking and neurotransmitter release in the presynaptic terminals. Pathologies related to misfolding and aggregation of α-syn are referred to as α-synucleinopathies, and they constitute a frequent cause of neurodegeneration. The most common α-synucleinopathy, Parkinson's disease (PD), is caused by abnormal accumulation of α-syn in the dopaminergic neurons of the midbrain. This results in protein overload, activation of endoplasmic reticulum (ER) stress, and, ultimately, neural cell apoptosis and neurodegeneration. To date, the available treatment options for PD are only symptomatic and rely on dopamine replacement therapy or palliative surgery. As the prevalence of PD has skyrocketed in recent years, there is a pending issue for development of new disease-modifying strategies. These include anti-aggregative agents that target α-syn directly (gene therapy, small molecules and immunization), indirectly (modulators of ER stress, oxidative stress and clearance pathways) or combine both actions (natural compounds). Herein, we provide an overview on the characteristic features of the structure and pathogenic mechanisms of α-syn that could be targeted with novel molecular-based therapies.

Keywords:  ER stress; Lewy bodies; Parkinson’s disease; disease-modifying strategies; fibrils; oligomers; protein aggregates; small-molecule inhibitors; α-synuclein; α-synucleinopathy

DOI:  https://doi.org/10.3390/pharmaceutics15082051
Curr Opin Struct Biol. 2023 Aug 19. pii: S0959-440X(23)00152-5. [Epub ahead of print]82 102678

Role of aberrant phase separation in pathological protein aggregation.

Pijush Chakraborty, Markus Zweckstetter.

Neurodegenerative diseases are associated with the pathological deposition of many different intrinsically disordered proteins or proteins with intrinsically disordered regions. Recent evidence suggests that these proteins can undergo liquid-liquid phase separation and also form membrane-less organelles in cells. Additionally, the biomolecular condensates formed by these proteins may undergo liquid-to-solid phase transition thereby maturating to amyloid fibrils, oligomeric species, or amorphous aggregates and contributing to the pathology of several neurodegenerative diseases. Here we discuss the role of phase separation of the neuronal proteins tau, α-synuclein, fused in sarcoma (FUS), and the transactive response DNA-binding protein of 43 kDa (TDP-43) that are associated with neurodegeneration in the context of pathological protein aggregation.

DOI: https://doi.org/10.1016/j.sbi.2023.102678
Cell Commun Signal. 2023 Aug 24. 21(1): 220

Calcineurin stimulation by Cnb1p overproduction mitigates protein aggregation and α-synuclein toxicity in a yeast model of synucleinopathy.

Srishti Chawla, Doryaneh Ahmadpour, Kara L Schneider, Navinder Kumar, Arthur Fischbach, Mikael Molin, Thomas Nystrom.

  The calcium-responsive phosphatase, calcineurin, senses changes in Ca2+ concentrations in a calmodulin-dependent manner. Here we report that under non-stress conditions, inactivation of calcineurin signaling or deleting the calcineurin-dependent transcription factor CRZ1 triggered the formation of chaperone Hsp100p (Hsp104p)-associated protein aggregates in Saccharomyces cerevisiae. Furthermore, calcineurin inactivation aggravated α-Synuclein-related cytotoxicity. Conversely, elevated production of the calcineurin activator, Cnb1p, suppressed protein aggregation and cytotoxicity associated with the familial Parkinson's disease-related mutant α-Synuclein A53T in a partly CRZ1-dependent manner. Activation of calcineurin boosted normal localization of both wild type and mutant α-synuclein to the plasma membrane, an intervention previously shown to mitigate α-synuclein toxicity in Parkinson's disease models. The findings demonstrate that calcineurin signaling, and Ca2+ influx to the vacuole, limit protein quality control in non-stressed cells and may have implications for elucidating to which extent aberrant calcineurin signaling contributes to the progression of Parkinson's disease(s) and other synucleinopathies. Video Abstract.

Keywords:  Calcineurin; Protein aggregation; Protein phosphatase 2B; Protein quality control; α-synuclein

DOI:  https://doi.org/10.1186/s12964-023-01242-w
J Nat Prod. 2023 Aug 23.

α-Synuclein Aggregation Inhibitory and Antiplasmodial Activity of Constituents from the Australian Tree Eucalyptus cloeziana.

Dale W Prebble, Darren C Holland, Francesca Ferretti, Joshua B Hayton, Vicky M Avery, George D Mellick, Anthony R Carroll.

Amyloid protein aggregates are linked to the progression of neurodegenerative conditions and may play a role in life stages of Plasmodium falciparum, the parasite responsible for malaria. We hypothesize that amyloid protein aggregation inhibitors may show antiplasmodial activity and vice versa. To test this hypothesis, we screened antiplasmodial active extracts from 25 Australian eucalypt flowers using a binding affinity mass spectrometry assay to identify molecules that bind to the Parkinson's disease-implicated protein α-syn. Myrtucommulone P (1) from a flower extract of Eucalyptus cloeziana was shown to have α-syn affinity and antiplasmodial activity and to inhibit α-syn aggregation. 1 exists as a mixture of four interconverting rotamers. Assignment of the NMR resonances of all four rotamers allowed us to define the relative configuration, conformations, and ratios of rotamers in solution. Four additional new compounds, cloeziones A-C (2-4) and cloeperoxide (5), along with three known compounds were also isolated from E. cloeziana. The structures of all compounds were elucidated using HRMS and NMR analysis, and the absolute configurations for 2-4 were determined by comparison of TDDFT-calculated and experimental ECD data. Compounds 1-3 displayed antiplasmodial activities between IC50 6.6 and 16 μM. The α-syn inhibitory and antiplasmodial activity of myrtucommulone P (1) supports the hypothesized link between antiamyloidogenic and antiplasmodial activity.

DOI: https://doi.org/10.1021/acs.jnatprod.3c00458
Mol Cell. 2023 Aug 22. pii: S1097-2765(23)00604-4. [Epub ahead of print]

Tuning Hsp104 specificity to selectively detoxify α-synuclein.

Korrie L Mack, Hanna Kim, Edward M Barbieri, JiaBei Lin, Sylvanne Braganza, Meredith E Jackrel, Jamie E DeNizio, Xiaohui Yan, Edward Chuang, Amber Tariq, Ryan R Cupo, Laura M Castellano, Kim A Caldwell, Guy A Caldwell, James Shorter.

  Hsp104 is an AAA+ protein disaggregase that solubilizes and reactivates proteins trapped in aggregated states. We have engineered potentiated Hsp104 variants to mitigate toxic misfolding of α-synuclein, TDP-43, and FUS implicated in fatal neurodegenerative disorders. Though potent disaggregases, these enhanced Hsp104 variants lack substrate specificity and can have unfavorable off-target effects. Here, to lessen off-target effects, we engineer substrate-specific Hsp104 variants. By altering Hsp104 pore loops that engage substrate, we disambiguate Hsp104 variants that selectively suppress α-synuclein toxicity but not TDP-43 or FUS toxicity. Remarkably, α-synuclein-specific Hsp104 variants emerge that mitigate α-synuclein toxicity via distinct ATPase-dependent mechanisms involving α-synuclein disaggregation or detoxification of soluble α-synuclein conformers. Importantly, both types of α-synuclein-specific Hsp104 variant reduce dopaminergic neurodegeneration in a C. elegans model of Parkinson's disease more effectively than non-specific variants. We suggest that increasing the substrate specificity of enhanced disaggregases could be applied broadly to tailor therapeutics for neurodegenerative disease.

Keywords:  Hsp104; Parkinson’s disease; alpha-synuclein; disaggregase; neurodegeneration; protein engineering

DOI:  https://doi.org/10.1016/j.molcel.2023.07.029
FEBS Lett. 2023 Aug 19.

Nucleocytoplasmic transport at the crossroads of proteostasis, neurodegeneration and neuroprotection.

Paulo A Ferreira.

  Nucleocytoplasmic transport comprises the multistep assembly, transport, and disassembly of protein and RNA cargoes entering and exiting nuclear pores. Accruing evidence supports that impairments to nucleocytoplasmic transport are a hallmark of neurodegenerative diseases. These impairments cause dysregulations in nucleocytoplasmic partitioning and proteostasis of nuclear transport receptors and client substrates that promote intracellular deposits - another hallmark of neurodegeneration. Disturbances in liquid-liquid phase separation (LLPS) between dense and dilute phases of biomolecules implicated in nucleocytoplasmic transport promote micrometer-scale coacervates, leading to proteinaceous aggregates. This Review provides historical and emerging principles of LLPS at the interface of nucleocytoplasmic transport, proteostasis, aging and noxious insults, whose dysregulations promote intracellular aggregates. E3 SUMO-protein ligase Ranbp2 constitutes the cytoplasmic filaments of nuclear pores, where it acts as a molecular hub for rate-limiting steps of nucleocytoplasmic transport. A vignette is provided on the roles of Ranbp2 in nucleocytoplasmic transport and at the intersection of proteostasis in the survival of photoreceptor and motor neurons under homeostatic and pathophysiological environments. Current unmet clinical needs are highlighted, including therapeutics aiming to manipulate aggregation-dissolution models of purported neurotoxicity in neurodegeneration.

Keywords:  Ran-binding protein 2; chaperone; cyclophilin; liquid-liquid phase separation; motoneuron; neurodegeneration; neuroprotection; nucleocytoplasmic transport; photoreceptor neuron; protein aggregation

DOI:  https://doi.org/10.1002/1873-3468.14722
Antioxidants (Basel). 2023 Aug 17. pii: 1628. [Epub ahead of print]12(8):

Roles of Oxidative Stress in Synaptic Dysfunction and Neuronal Cell Death in Alzheimer's Disease.

Germán Plascencia-Villa, George Perry.

  Alzheimer's disease (AD) is a brain disorder that progressively undermines memory and thinking skills by affecting the hippocampus and entorhinal cortex. The main histopathological hallmarks of AD are the presence of abnormal protein aggregates (Aβ and tau), synaptic dysfunction, aberrant proteostasis, cytoskeletal abnormalities, altered energy homeostasis, DNA and RNA defects, inflammation, and neuronal cell death. However, oxidative stress or oxidative damage is also evident and commonly overlooked or considered a consequence of the advancement of dementia symptoms. The control or onset of oxidative stress is linked to the activity of the amyloid-β peptide, which may serve as both antioxidant and pro-oxidant molecules. Furthermore, oxidative stress is correlated with oxidative damage to proteins, nucleic acids, and lipids in vulnerable cell populations, which ultimately lead to neuronal death through different molecular mechanisms. By recognizing oxidative stress as an integral feature of AD, alternative therapeutic or preventive interventions are developed and tested as potential or complementary therapies for this devastating neurodegenerative disease.

Keywords:  Alzheimer’s disease; antioxidants; free radicals; neurodegeneration; neurons; oxidants; oxidative damage; oxidative stress

DOI:  https://doi.org/10.3390/antiox12081628
Biochem Pharmacol. 2023 Aug 19. pii: S0006-2952(23)00351-9. [Epub ahead of print] 115760

Proteostasis plays an important role in demyelinating Charcot Marie Tooth disease.

Karen Libberecht, Tim Vangansewinkel, Ludo Van Den Bosch, Ivo Lambrichts, Esther Wolfs.

  Type 1 Charcot-Marie-Tooth disease (CMT1) is the most common demyelinating peripheral neuropathy. Patients suffer from progressive muscle weakness and sensory problems. The underlying disease mechanisms of CMT1 are still unclear and no therapy is currently available, hence patients completely rely on supportive care. Balancing protein levels is a complex multistep process fundamental to maintain cells in their healthy state and a disrupted proteostasis is a hallmark of several neurodegenerative diseases. When protein misfolding occurs, protein quality control systems are activated such as chaperones, the lysosomal-autophagy system and proteasomal degradation to ensure proper degradation. However, in pathological circumstances, these mechanisms are overloaded and thereby become inefficient to clear the load of misfolded proteins. Recent evidence strongly indicates that a disbalance in proteostasis plays an important role in several forms of CMT1. In this review, we present an overview of the protein quality control systems, their role in CMT1, and potential treatment strategies to restore proteostasis.

Keywords:  Charcot-Marie-Tooth disease; Schwann cells; autophagy; neurodegenerative disease; protein misfolding; proteostasis

DOI:  https://doi.org/10.1016/j.bcp.2023.115760
Antioxidants (Basel). 2023 Aug 21. pii: 1648. [Epub ahead of print]12(8):

The Unfolded Protein Response: A Double-Edged Sword for Brain Health.

Magdalena Gebert, Jakub Sławski, Leszek Kalinowski, James F Collawn, Rafal Bartoszewski.

  Efficient brain function requires as much as 20% of the total oxygen intake to support normal neuronal cell function. This level of oxygen usage, however, leads to the generation of free radicals, and thus can lead to oxidative stress and potentially to age-related cognitive decay and even neurodegenerative diseases. The regulation of this system requires a complex monitoring network to maintain proper oxygen homeostasis. Furthermore, the high content of mitochondria in the brain has elevated glucose demands, and thus requires a normal redox balance. Maintaining this is mediated by adaptive stress response pathways that permit cells to survive oxidative stress and to minimize cellular damage. These stress pathways rely on the proper function of the endoplasmic reticulum (ER) and the activation of the unfolded protein response (UPR), a cellular pathway responsible for normal ER function and cell survival. Interestingly, the UPR has two opposing signaling pathways, one that promotes cell survival and one that induces apoptosis. In this narrative review, we discuss the opposing roles of the UPR signaling pathways and how a better understanding of these stress pathways could potentially allow for the development of effective strategies to prevent age-related cognitive decay as well as treat neurodegenerative diseases.

Keywords:  brain; calcium; endoplasmic reticulum stress; mitochondria unfolded protein response; neurodegeneration; nitrosative stress; oxidative stress; oxygen homeostasis; proteostasis

DOI:  https://doi.org/10.3390/antiox12081648