bims-proned 2024-04-07 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2024–04–07
seven papers selected by
Verena Kohler, Umeå University

Single-Domain Antibody-Based Protein Degrader for Synucleinopathies.
Role of autophagy and proteostasis in neurodegenerative diseases: Exploring the therapeutic interventions.
Heterotypic Seeding Generates Mixed Amyloid Polymorphs.
VCP/p97 mediates nuclear targeting of non-ER-imported prion protein to maintain proteostasis.
Development of a pan-tau multivalent nanobody that binds tau aggregation motifs and recognizes pathological tau aggregates.
Tetramethylpyrazine Nitrone Promotes the Clearance of Alpha-Synuclein via Nrf2-Mediated Ubiquitin-Proteasome System Activation.
Impact of histone deacetylase inhibition and arimoclomol on heat shock protein expression and disease biomarkers in primary culture models of familial ALS.

bioRxiv. 2024 Mar 13. pii: 2024.03.11.584473. [Epub ahead of print]

Single-Domain Antibody-Based Protein Degrader for Synucleinopathies.

Yixiang Jiang, Yan Lin, Amber M Tetlow, Ruimin Pan, Changyi Ji, Xiang-Peng Kong, Erin E Congdon, Einar M Sigurdsson.

Synucleinopathies are a group of neurodegenerative diseases characterized by the accumulation of α-synuclein (α-syn) in the brain, leading to motor and neuropsychiatric symptoms. Currently, there are no known cures for synucleinopathies, and treatments mainly focus on symptom management. In this study, we developed a single-domain antibody (sdAb)-based protein degrader with features designed to enhance proteasomal degradation of α-syn. This sdAb derivative targets both α-syn and Cereblon (CRBN), a substrate-receptor for the E3-ubiquitin ligase CRL4 CRBN , and thereby induces α-syn ubiquitination and proteasomal degradation. Our results indicate that this therapeutic ligand enhances proteasomal degradation of α-syn, in addition to the endogenous lysosomal degradation machinery. By promoting proteasomal degradation of α-syn, we improved clearance of α-syn in primary culture and mouse models of synucleinopathy. These findings indicate that our sdAb-based protein degrader is a promising therapeutic for synucleinopathies. Considering that only a small percentage of antibodies enter the brain, more potent sdAbs with greater brain entry than whole antibodies could enhance clinical benefits of antibody-based therapies.

DOI: https://doi.org/10.1101/2024.03.11.584473
Chem Biol Drug Des. 2024 Apr;103(4): e14515

Role of autophagy and proteostasis in neurodegenerative diseases: Exploring the therapeutic interventions.

Surbhi Panwar, Prerna Uniyal, Neelima Kukreti, Afreen Hashmi, Shivani Verma, Aanchal Arya, Gaurav Joshi.

  Neurodegenerative disorders are devastating disorders characterized by gradual loss of neurons and cognition or mobility impairment. The common pathological features of these diseases are associated with the accumulation of misfolded or aggregation of proteins. The pivotal roles of autophagy and proteostasis in maintaining cellular health and preventing the accumulation of misfolded proteins, which are associated with neurodegenerative diseases like Huntington's disease (HD), Alzheimer's disease (AD), and Parkinson's disease (PD). This article presents an in-depth examination of the interplay between autophagy and proteostasis, highlighting how these processes cooperatively contribute to cellular homeostasis and prevent pathogenic protein aggregate accumulation. Furthermore, the review emphasises the potential therapeutic implications of targeting autophagy and proteostasis to mitigate neurodegenerative diseases. While advancements in research hold promise for developing novel treatments, the article also addresses the challenges and complexities associated with modulating these intricate cellular pathways. Ultimately, advancing understanding of the underlying mechanism of autophagy and proteostasis in neurodegenerative disorders provides valuable insights into potential therapeutic avenues and future research directions.

Keywords:  cellular homeostatis; neurodegenerative disorders; pathogenesis; proteostasis

DOI:  https://doi.org/10.1111/cbdd.14515
bioRxiv. 2024 Mar 17. pii: 2024.03.15.585264. [Epub ahead of print]

Heterotypic Seeding Generates Mixed Amyloid Polymorphs.

S Banerjee, D Baghel, H O Edmonds, Ayanjeet Ghosh.

  Aggregation of the amyloid β (Aβ) peptide into fibrils represents one of the major biochemical pathways underlying the development of Alzheimer's disease (AD). Extensive studies have been carried out to understand the role of fibrillar seeds on the overall kinetics of amyloid aggregation. However, the precise effect of seeds that are structurally or sequentially different from Aβ on the structure of the resulting amyloid aggregates is yet to be fully understood. In this work, we use nanoscale infrared spectroscopy to probe the spectral facets of individual aggregates formed by aggregating Aβ42 with antiparallel fibrillar seeds of Aβ (16-22) and E22Q Aβ (1-40) Dutch mutant and demonstrate that Aβ can form heterotypic or mixed polymorphs that deviate significantly from its expected parallel cross β structure. We further show that formation of heterotypic aggregates is not limited to coaggregation of Aβ and its isomers, and that the former can form heterotypic fibrils with alpha synuclein and brain protein lysates. These findings highlight the complexity of Aβ aggregation in AD and underscore the need to explore how Aβ interacts with other brain components, which is crucial for developing better therapeutic strategies for AD.

Keywords:  AFM-IR; Alzheimer’s disease; amyloid beta; infrared spectroscopy; nanoscale spectroscopy; protein aggregation

DOI:  https://doi.org/10.1101/2024.03.15.585264
Life Sci Alliance. 2024 Jun;pii: e202302456. [Epub ahead of print]7(6):

VCP/p97 mediates nuclear targeting of non-ER-imported prion protein to maintain proteostasis.

Papiya Banik, Koustav Ray, Janine Kamps, Qi-Yin Chen, Hendrik Luesch, Konstanze F Winklhofer, Jörg Tatzelt.

Mistargeting of secretory proteins in the cytosol can trigger their aggregation and subsequent proteostasis decline. We have identified a VCP/p97-dependent pathway that directs non-ER-imported prion protein (PrP) into the nucleus to prevent the formation of toxic aggregates in the cytosol. Upon impaired translocation into the ER, PrP interacts with VCP/p97, which facilitates nuclear import mediated by importin-ß. Notably, the cytosolic interaction of PrP with VCP/p97 and its nuclear import are independent of ubiquitination. In vitro experiments revealed that VCP/p97 binds non-ubiquitinated PrP and prevents its aggregation. Inhibiting binding of PrP to VCP/p97, or transient proteotoxic stress, promotes the formation of self-perpetuating and partially proteinase resistant PrP aggregates in the cytosol, which compromised cellular proteostasis and disrupted further nuclear targeting of PrP. In the nucleus, RNAs keep PrP in a soluble and non-toxic conformation. Our study revealed a novel ubiquitin-independent role of VCP/p97 in the nuclear targeting of non-imported secretory proteins and highlights the impact of the chemical milieu in triggering protein misfolding.

DOI: https://doi.org/10.26508/lsa.202302456
Biotechnol Prog. 2024 Apr 03. e3463

Development of a pan-tau multivalent nanobody that binds tau aggregation motifs and recognizes pathological tau aggregates.

Nikki McArthur, Bokyung Kang, Felix G Rivera Moctezuma, Akber T Shaikh, Kathryn Loeffler, Nemil N Bhatt, Madison Kidd, Jennifer M Zupancic, Alec A Desai, Naima Djeddar, Anton Bryksin, Peter M Tessier, Rakez Kayed, Levi B Wood, Ravi S Kane.

  Alzheimer's disease and other tauopathies are characterized by the misfolding and aggregation of the tau protein into oligomeric and fibrillar structures. Antibodies against tau play an increasingly important role in studying these neurodegenerative diseases and the generation of tools to diagnose and treat them. The development of antibodies that recognize tau protein aggregates, however, is hindered by complex immunization and antibody selection strategies and limitations to antigen presentation. Here, we have taken a facile approach to identify single-domain antibodies, or nanobodies, that bind to many forms of tau by screening a synthetic yeast surface display nanobody library against monomeric tau and creating multivalent versions of our lead nanobody, MT3.1, to increase its avidity for tau aggregates. We demonstrate that MT3.1 binds to tau monomer, oligomers, and fibrils, as well as pathogenic tau from a tauopathy mouse model, despite being identified through screens against monomeric tau. Through epitope mapping, we discovered binding epitopes of MT3.1 contain the key motif VQIXXK which drives tau aggregation. We show that our bivalent and tetravalent versions of MT3.1 have greatly improved binding ability to tau oligomers and fibrils compared to monovalent MT3.1. Our results demonstrate the utility of our nanobody screening and multivalent design approach in developing nanobodies that bind amyloidogenic protein aggregates. This approach can be extended to the generation of multivalent nanobodies that target other amyloid proteins and has the potential to advance the research and treatment of neurodegenerative diseases.

Keywords:  Alzheimer's disease; aggregate; amyloid; multivalency; nanobody; tau; yeast surface display

DOI:  https://doi.org/10.1002/btpr.3463
Neuromolecular Med. 2024 Apr 03. 26(1): 9

Tetramethylpyrazine Nitrone Promotes the Clearance of Alpha-Synuclein via Nrf2-Mediated Ubiquitin-Proteasome System Activation.

Baojian Guo, Chengyou Zheng, Jie Cao, Xiaoling Qiu, Fangcheng Luo, Haitao Li, Simon Mingyuan Lee, Xifei Yang, Gaoxiao Zhang, Yewei Sun, Zaijun Zhang, Yuqiang Wang.

  Aggregation of α-synuclein (α-syn) and α-syn cytotoxicity are hallmarks of sporadic and familial Parkinson's disease (PD). Nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-dependent enhancement of the expression of the 20S proteasome core particles (20S CPs) and regulatory particles (RPs) increases proteasome activity, which can promote α-syn clearance in PD. Activation of peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) may reduce oxidative stress by strongly inducing Nrf2 gene expression. In the present study, tetramethylpyrazine nitrone (TBN), a potent-free radical scavenger, promoted α-syn clearance by the ubiquitin-proteasome system (UPS) in cell models overexpressing the human A53T mutant α-syn. In the α-syn transgenic mice model, TBN improved motor impairment, decreased the products of oxidative damage, and down-regulated the α-syn level in the serum. TBN consistently up-regulated PGC-1α and Nrf2 expression in tested models of PD. Additionally, TBN similarly enhanced the proteasome 20S subunit beta 8 (Psmb8) expression, which is linked to chymotrypsin-like proteasome activity. Furthermore, TBN increased the mRNA levels of both the 11S RPs subunits Pa28αβ and a proteasome chaperone, known as the proteasome maturation protein (Pomp). Interestingly, specific siRNA targeting of Nrf2 blocked TBN's effects on Psmb8, Pa28αβ, Pomp expression, and α-syn clearance. In conclusion, TBN promotes the clearance of α-syn via Nrf2-mediated UPS activation, and it may serve as a potentially disease-modifying therapeutic agent for PD.

Keywords:  Nuclear factor erythroid-2-related factor 2; Parkinson’s disease; Peroxisome proliferator-activated receptor γ co-activator 1α; Tetramethylpyrazine nitrone; Ubiquitin–proteasome system; α-synuclein

DOI:  https://doi.org/10.1007/s12017-024-08775-4
Cell Stress Chaperones. 2024 Apr 01. pii: S1355-8145(24)00062-2. [Epub ahead of print]

Impact of histone deacetylase inhibition and arimoclomol on heat shock protein expression and disease biomarkers in primary culture models of familial ALS.

Mario Fernández Comaduran, Sandra Minotti, Suleima Jacob-Tomas, Javeria Rizwan, Nancy Larochelle, Richard Robitaille, Chantelle F Sephton, M Vera, Josephine N Nalbantoglu, Heather D Durham.

  Protein misfolding and mislocalization are common themes in neurodegenerative disorders, including the motor neuron disease, amyotrophic lateral sclerosis (ALS). Maintaining proteostasis is a crosscutting therapeutic target, including upregulation of heat shock proteins (HSP) to increase chaperoning capacity. Motor neurons have a high threshold for upregulating stress inducible HSPA1A, but constitutively express high levels of HSPA8. This study compared expression of these HSPs in cultured motor neurons expressing three variants linked to familial ALS: TDP-43G348C, FUSR521G or SOD1G93A. All variants were poor inducers of Hspa1a, and reduced levels of Hspa8 mRNA and protein, indicating multiple compromises in chaperoning capacity. To promote HSP expression, cultures were treated with the putative HSP co-inducer, arimoclomol, class I histone deacetylase (HDAC) inhibitors to promote active chromatin for transcription, and the combination. Treatments had variable, often different effects on expression of Hspa1a and Hspa8, depending on the ALS variant expressed, mRNA distribution (somata and dendrites), and biomarker of toxicity measured (histone acetylation, maintaining nuclear TDP-43 and the nBAF chromatin remodeling complex component Brg1, mitochondrial transport, FUS aggregation). Overall, HDAC inhibition alone was effective on more measures than arimoclomol. As in the FUS model, arimoclomol failed to induce HSPA1A or preserve Hspa8 mRNA In the TDP-43 model, despite preserving nuclear TDP-43 and Brg1, indicating neuroprotective properties other than HSP induction. The data speak to the complexity of drug mechanisms against multiple biomarkers of ALS pathogenesis, as well as to the importance of HSPA8 for neuronal proteostasis in both somata and dendrites.

Keywords:  amyotrophic lateral sclerosis; arimoclomol; chromatin remodeling; heat shock protein; histone deacetylase inhibitor

DOI:  https://doi.org/10.1016/j.cstres.2024.03.010