bims-proned 2024-09-01 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2024–09–01
eightteen papers selected by
Verena Kohler, Umeå University

HSP110 is a modulator of amyloid beta (Aβ) aggregation and proteotoxicity.
A Cationic Zn-Phthalocyanine Turns Alzheimer's Amyloid β Aggregates into Non-Toxic Oligomers and Inhibits Neurotoxicity in Culture.
dGAE(297-391) Tau Fragment Promotes Formation of Chronic Traumatic Encephalopathy-Like Tau Filaments.
On the pH-dependence of α-synuclein amyloid polymorphism and the role of secondary nucleation in seed-based amyloid propagation.
Interaction of full-length Tau with negatively charged lipid membranes leads to polymorphic aggregates.
Oxidative Cysteine Post Translational Modifications Drive the Redox Code Underlying Neurodegeneration and Amyotrophic Lateral Sclerosis.
Phosphoryl group wires stabilize pathological tau fibrils as revealed by multiple quantum spin counting NMR.
Impact of NaCl on Monoclonal Antibody Aggregation Induced by Agitation.
Extending computational protein design to intrinsically disordered proteins.
Endoplasmic reticulum stress in diseases.
Galantamine suppresses α-synuclein aggregation by inducing autophagy via the activation of α7 nicotinic acetylcholine receptors.
Single acetylation-mimetic mutation in TDP-43 Nuclear Localization Signal disrupts importin α1/β signaling.
Quantitative 3D histochemistry reveals region-specific amyloid-β reduction by the antidiabetic drug netoglitazone.
Phase Separation of SARS-CoV-2 Nucleocapsid Protein with TDP-43 Is Dependent on C-Terminus Domains.
Novel strategies in Parkinson's disease treatment: a review.
Metformin Lysosomal Targeting: A Novel Aspect to Be Investigated for Metformin Repurposing in Neurodegenerative Diseases?
Role of Lipids in the Pathogenesis of Parkinson's Disease.
The mechanisms of Ca2+ regulating autophagy and its research progress in neurodegenerative diseases: A review.

J Neurochem. 2024 Aug 23.

HSP110 is a modulator of amyloid beta (Aβ) aggregation and proteotoxicity.

Sabrina Montresor, Maria Lucia Pigazzini, Sudarson Baskaran, Mira Sleiman, Govinda Adhikari, Lukas Basilicata, Luca Secker, Natascha Jacob, Yara Ehlert, Anushree Kelkar, Gurleen Kaur Kalsi, Niraj Kulkarni, Paul Spellerberg, Janine Kirstein.

  Chaperones safeguard protein homeostasis by promoting folding and preventing aggregation. HSP110 is a cytosolic chaperone that functions as a nucleotide exchange factor for the HSP70 cycle. Together with HSP70 and a J-domain protein (JDP), HSP110 maintains protein folding and resolubilizes aggregates. Interestingly, HSP110 is vital for the HSP70/110/JDP-mediated disaggregation of amyloidogenic proteins implicated in neurodegenerative diseases (i.e., α-synuclein, HTT, and tau). However, despite its abundance, HSP110 remains still an enigmatic chaperone, and its functional spectrum is not very well understood. Of note, the disaggregation activity of neurodegenerative disease-associated amyloid fibrils showed both beneficial and detrimental outcomes in vivo. To gain a more comprehensive understanding of the chaperone HSP110 in vivo, we analyzed its role in neuronal proteostasis and neurodegeneration in C. elegans. Specifically, we investigated the role of HSP110 in the regulation of amyloid beta peptide (Aβ) aggregation using an established Aβ-C. elegans model that mimics Alzheimer's disease pathology. We generated a novel C. elegans model that over-expresses hsp-110 pan-neuronally, and we also depleted hsp-110 by RNAi-mediated knockdown. We assessed Aβ aggregation in vivo and in situ by fluorescence lifetime imaging. We found that hsp-110 over-expression exacerbated Aβ aggregation and appeared to reduce the conformational variability of the Aβ aggregates, whereas hsp-110 depletion reduced aggregation more significantly in the IL2 neurons, which marked the onset of Aβ aggregation. HSP-110 also plays a central role in growth and fertility as its over-expression compromises nematode physiology. In addition, we found that HSP-110 modulation affects the autophagy pathway. While hsp-110 over-expression impairs the autophagic flux, a depletion enhances it. Thus, HSP-110 regulates multiple nodes of the proteostasis network to control amyloid protein aggregation, disaggregation, and autophagic clearance.

Keywords:  Abeta; C. elegans; aggregation; chaperones; proteostasis

DOI:  https://doi.org/10.1111/jnc.16214
Int J Mol Sci. 2024 Aug 16. pii: 8931. [Epub ahead of print]25(16):

A Cationic Zn-Phthalocyanine Turns Alzheimer's Amyloid β Aggregates into Non-Toxic Oligomers and Inhibits Neurotoxicity in Culture.

Abdullah Md Sheikh, Shatera Tabassum, Shozo Yano, Fatema Binte Abdullah, Ruochen Wang, Takahisa Ikeue, Atsushi Nagai.

  Amyloid β peptide (Aβ) aggregation and deposition are considered the main causes of Alzheimer's disease. In a previous study, we demonstrated that anionic Zn-phthalocyanine (ZnPc) can interact with the Aβ peptide and inhibit the fibril-formation process. However, due to the inability of anionic ZnPc to cross the intact blood-brain barrier, we decided to explore the interaction of cationic methylated Zn-phthalocyanine (cZnPc) with the peptide. Using a ThT fluorescence assay, we observed that cZnPc dose-dependently and time-dependently inhibited Aβ1-42 fibril levels under in vitro fibril-formation conditions. Electron microscopy revealed that it caused Aβ1-42 peptides to form small aggregates. Western blotting and dot immunoblot oligomer experiments demonstrated that cZnPc increased rather than decreased the levels of oligomers from the very early stages of incubation. A binding assay confirmed that cZnPc could bind with the peptide. Docking simulations indicated that the oligomer species of Aβ1-42 had a higher ability to interact with cZnPc. ANS fluorescence assay results indicated that cZnPc did not affect the hydrophobicity of the peptide. However, cZnPc significantly increased intrinsic tyrosine fluorescence of the peptide after 8 h of incubation in fibril-formation conditions. Importantly, cell culture experiments demonstrated that cZnPc did not exhibit any toxicity up to a concentration of 10 µM. Instead, it protected a neuronal cell line from Aβ1-42-induced toxicity. Thus, our results suggest that cZnPc can affect the aggregation process of Aβ1-42, rendering it non-toxic, which could be crucial for the therapy of Alzheimer's disease.

Keywords:  Alzheimer’s disease; amyloid β; amyloid β binding; fibril formation; neurodegeneration; oligomers

DOI:  https://doi.org/10.3390/ijms25168931
Angew Chem Int Ed Engl. 2024 Aug 26. e202407821

dGAE(297-391) Tau Fragment Promotes Formation of Chronic Traumatic Encephalopathy-Like Tau Filaments.

Kristine Kitoka, Alons Lends, Gytis Kucinskas, Anna Lina Bula, Lukas Krasauskas, Vytautas Smirnovas, Monika Zilkova, Branislav Kovacech, Rostislav Skrabana, Jozef Hritz, Kristaps Jaudzems.

  The microtubule-associated protein tau forms disease-specific filamentous aggregates in several different neurodegenerative diseases. In order to understand how tau undergoes misfolding into a specific filament type and to control this process for drug development purposes, it is crucial to study in vitro tau aggregation methods and investigate the structures of the obtained filaments at the atomic level. Here, we used the tau fragment dGAE, which aggregates spontaneously, to seed the formation of full-length tau filaments. The structures of dGAE and full-length tau filaments were investigated by magic-angle spinning (MAS) solid-state NMR, showing that dGAE allows propagation of a chronic traumatic encephalopathy (CTE)-like fold to the full-length tau. The obtained filaments efficiently seeded tau aggregation in HEK293T cells. This work demonstrates that in vitro preparation of disease-specific types of full-length tau filaments is feasible.

Keywords:  NMR Spectroscopy; Tau protein; dGAE fragment; filamentous aggregates; tauopathies

DOI:  https://doi.org/10.1002/anie.202407821
Elife. 2024 Aug 28. pii: RP93562. [Epub ahead of print]12

On the pH-dependence of α-synuclein amyloid polymorphism and the role of secondary nucleation in seed-based amyloid propagation.

Lukas Frey, Dhiman Ghosh, Bilal M Qureshi, David Rhyner, Ricardo Guerrero-Ferreira, Aditya Pokharna, Witek Kwiatkowski, Tetiana Serdiuk, Paola Picotti, Roland Riek, Jason Greenwald.

  The aggregation of the protein α-synuclein is closely associated with several neurodegenerative disorders and as such the structures of the amyloid fibril aggregates have high scientific and medical significance. However, there are dozens of unique atomic-resolution structures of these aggregates, and such a highly polymorphic nature of the α-synuclein fibrils hampers efforts in disease-relevant in vitro studies on α-synuclein amyloid aggregation. In order to better understand the factors that affect polymorph selection, we studied the structures of α-synuclein fibrils in vitro as a function of pH and buffer using cryo-EM helical reconstruction. We find that in the physiological range of pH 5.8-7.4, a pH-dependent selection between Type 1, 2, and 3 polymorphs occurs. Our results indicate that even in the presence of seeds, the polymorph selection during aggregation is highly dependent on the buffer conditions, attributed to the non-polymorph-specific nature of secondary nucleation. We also uncovered two new polymorphs that occur at pH 7.0 in phosphate-buffered saline. The first is a monofilament Type 1 fibril that highly resembles the structure of the juvenile-onset synucleinopathy polymorph found in patient-derived material. The second is a new Type 5 polymorph that resembles a polymorph that has been recently reported in a study that used diseased tissues to seed aggregation. Taken together, our results highlight the shallow amyloid energy hypersurface that can be altered by subtle changes in the environment, including the pH which is shown to play a major role in polymorph selection and in many cases appears to be the determining factor in seeded aggregation. The results also suggest the possibility of producing disease-relevant structure in vitro.

Keywords:  E. coli; Parkinson's disease; amyloid; human; molecular biophysics; polymorphism; structural biology; α-synuclein

DOI:  https://doi.org/10.7554/eLife.93562
Nanoscale. 2024 Aug 27.

Interaction of full-length Tau with negatively charged lipid membranes leads to polymorphic aggregates.

Vicky Ury-Thiery, Yann Fichou, Isabel Alves, Michael Molinari, Sophie Lecomte, Cécile Feuillie.

The Tau protein is implicated in various diseases collectively known as tauopathies, including Alzheimer's disease and frontotemporal dementia. The precise mechanism underlying Tau pathogenicity remains elusive. Recently, the role of lipids has garnered interest due to their implications in Tau aggregation, secretion, uptake, and pathogenic dysregulation. Previous investigations have highlighted critical aspects: (i) Tau's tendency to aggregate into fibers when interacting with negatively charged lipids, (ii) its ability to form structured species upon contact with anionic membranes, and (iii) the potential disruption of the membrane upon Tau binding. In this study, we examine the disease-associated P301L mutation of the 2N4R isoform of Tau and its effects on membranes composed on phosphatidylserine (PS) lipids. Aggregation studies and liposome leakage assays demonstrate Tau's ability to bind to anionic lipid vesicles, leading to membrane disruption. Attenuated total reflection Fourier-transform infrared spectroscopy (ATR-FTIR) reveals the accumulation of Tau on the membrane surface without protein insertion, structuration, or lipid removal. Plasmon waveguide resonance (PWR) demonstrates a strong binding of Tau on PS bilayers with an apparent Kd in the micromolar range, indicating the deposition of a thick protein layer. Atomic force microscopy (AFM) real-time imaging allows the observation of partial lipid solubilization and the deposition of polymorphic aggregates in the form of thick patches and fibrillary structures resembling amyloid fibers, which could grow from a combination of extracted anionic phospholipids from the membrane and Tau protein. This study deepens our understanding of full-length Tau's multifaceted interactions with lipids, shedding light on potential mechanisms leading to the formation of pathogenic Tau assemblies.

DOI: https://doi.org/10.1039/d4nr01343c
Antioxidants (Basel). 2024 Jul 23. pii: 883. [Epub ahead of print]13(8):

Oxidative Cysteine Post Translational Modifications Drive the Redox Code Underlying Neurodegeneration and Amyotrophic Lateral Sclerosis.

Anna Percio, Michela Cicchinelli, Domiziana Masci, Mariagrazia Summo, Andrea Urbani, Viviana Greco.

  Redox dysregulation, an imbalance between oxidants and antioxidants, is crucial in the pathogenesis of various neurodegenerative diseases. Within this context, the "redoxome" encompasses the network of redox molecules collaborating to maintain cellular redox balance and signaling. Among these, cysteine-sensitive proteins are fundamental for this homeostasis. Due to their reactive thiol groups, cysteine (Cys) residues are particularly susceptible to oxidative post-translational modifications (PTMs) induced by free radicals (reactive oxygen, nitrogen, and sulfur species) which profoundly affect protein functions. Cys-PTMs, forming what is referred to as "cysteinet" in the redox proteome, are essential for redox signaling in both physiological and pathological conditions, including neurodegeneration. Such modifications significantly influence protein misfolding and aggregation, key hallmarks of neurodegenerative diseases such as Alzheimer's, Parkinson's, and notably, amyotrophic lateral sclerosis (ALS). This review aims to explore the complex landscape of cysteine PTMs in the cellular redox environment, elucidating their impact on neurodegeneration at protein level. By investigating specific cysteine-sensitive proteins and the regulatory networks involved, particular emphasis is placed on the link between redox dysregulation and ALS, highlighting this pathology as a prime example of a neurodegenerative disease wherein such redox dysregulation is a distinct hallmark.

Keywords:  amyotrophic lateral sclerosis; cysteine PTMs; mitochondria; neurodegeneration; proteome; redox dysregulation

DOI:  https://doi.org/10.3390/antiox13080883
bioRxiv. 2024 Aug 17. pii: 2024.08.14.606685. [Epub ahead of print]

Phosphoryl group wires stabilize pathological tau fibrils as revealed by multiple quantum spin counting NMR.

Lokeswara Rao Potnuru, Austin DuBose, Mesopotamia S Nowotarski, Michael Vigers, Boqin Zhang, Chung-Ta Han, Songi Han.

  Hyperphosphorylation of the protein tau is one of the biomarkers of neurodegenerative diseases in the category of tauopathies. However, the molecular level, mechanistic, role of this common post-translational modification (PTM) in enhancing or reducing the aggregation propensity of tau is unclear, especially considering that combinatorial phosphorylation of multiple sites can have complex, non-additive, effects on tau protein aggregation. Since tau proteins stack in register and parallel to elongate into pathological fibrils, phosphoryl groups from adjacent tau strands with 4.8 Å separation must find an energetically favorable spatial arrangement. At first glance, this appears to be an unfavorable configuration due to the proximity of negative charges between phosphate groups from adjacent neighboring tau fibrils. However, this study tests a counterhypothesis that phosphoryl groups within the fibril core-forming segments favorably assemble into highly ordered, hydrogen-bonded, one-dimensionally extended wires under biologically relevant conditions. We selected two phosphorylation sites associated with neurodegeneration, serine 305 (S305p) and tyrosine 310 (Y310p), on a model tau peptide jR2R3-P301L (tau295-313) spanning the R2/R3 splice junction of tau, that readily aggregate into a fibril with characteristics of a seed-competent mini prion. Using multiple quantum spin counting (MQ-SC) by 31P solid-state NMR of phosphorylated jR2R3-P301L tau peptide fibrils, enhanced by dynamic nuclear polarization, we find that at least six phosphorous spins must neatly arrange in 1D within fibrils or in 2D within a protofibril to yield the experimentally observed MQ-coherence orders of four. We found that S305p stabilizes the tau fibrils and leads to more seeding-competent fibrils compared to jR2R3 P301L or Y310p. This study introduces a new concept that phosphorylation of residues within a core forming tau segment can mechanically facilitate fibril registry and stability due a hitherto unrecognized role of phosphoryl groups to form highly ordered, extended, 1D wires that stabilize pathological tau fibrils.

Keywords:  31P solid-state NMR; DNP; multi-quantum spin counting; phosphorylation; tauopathy

DOI:  https://doi.org/10.1101/2024.08.14.606685
PDA J Pharm Sci Technol. 2024 Aug 23. 78(4): 465-474

Impact of NaCl on Monoclonal Antibody Aggregation Induced by Agitation.

Justin K Y Hong, Wei Liu, Kai Zheng.

  Monoclonal antibodies (mAbs) are a successful class of therapeutics, but their development can be challenging due to the risk of degradation that could happen during manufacturing, storage, and clinical use. One of the common causes of degradation is agitation stress from transportation and clinical handling, which increases interfacial stresses to mAbs. For example, the preparation of the dose solution prior to administration often requires diluting therapeutic mAbs in intravenous (IV) infusion bags containing normal saline, which can substantially reduce the level of protective surfactant and increase the level of salt in mAb solutions. Then the interfacial stress in the subsequent transportation of IV bags can cause mAb aggregation or even particle formation. To better understand the complex interplay between dilution, interfacial stress, and salt, we studied the impact of sodium chloride (NaCl) on the aggregation of two mAbs under agitation stress. We found that the presence of NaCl accelerates the aggregation of both mAbs, but the aggregation mechanism, morphology, and reversibility are very different. Our results clearly highlight the impact of salt on mAb stability at the clinical in-use condition. We believe this study further increases our understanding of protein aggregation mediated by interfacial stresses and brings valuable insights to support development of mAb formulations for patients.

Keywords:  Agitation stress; Air-liquid interface; Monoclonal antibody; Pharmaceutical development; Protein aggregation

DOI:  https://doi.org/10.5731/pdajpst.2023.012860
Sci Adv. 2024 Aug 30. 10(35): eadr3239

Extending computational protein design to intrinsically disordered proteins.

Paul Robustelli.

Advances in the accuracy and throughput of molecular simulations usher in a new era in the structural biology of disordered proteins.

DOI: https://doi.org/10.1126/sciadv.adr3239
MedComm (2020). 2024 Sep;5(9): e701

Endoplasmic reticulum stress in diseases.

Yingying Liu, Chunling Xu, Renjun Gu, Ruiqin Han, Ziyu Li, Xianrong Xu.

  The endoplasmic reticulum (ER) is a key organelle in eukaryotic cells, responsible for a wide range of vital functions, including the modification, folding, and trafficking of proteins, as well as the biosynthesis of lipids and the maintenance of intracellular calcium homeostasis. A variety of factors can disrupt the function of the ER, leading to the aggregation of unfolded and misfolded proteins within its confines and the induction of ER stress. A conserved cascade of signaling events known as the unfolded protein response (UPR) has evolved to relieve the burden within the ER and restore ER homeostasis. However, these processes can culminate in cell death while ER stress is sustained over an extended period and at elevated levels. This review summarizes the potential role of ER stress and the UPR in determining cell fate and function in various diseases, including cardiovascular diseases, neurodegenerative diseases, metabolic diseases, autoimmune diseases, fibrotic diseases, viral infections, and cancer. It also puts forward that the manipulation of this intricate signaling pathway may represent a novel target for drug discovery and innovative therapeutic strategies in the context of human diseases.

Keywords:  diseases; endoplasmic reticulum stress (ER stress); therapeutic strategies ; unfolded protein response (UPR)

DOI:  https://doi.org/10.1002/mco2.701
J Pharmacol Sci. 2024 Oct;pii: S1347-8613(24)00053-7. [Epub ahead of print]156(2): 102-114

Galantamine suppresses α-synuclein aggregation by inducing autophagy via the activation of α7 nicotinic acetylcholine receptors.

Sora Nozaki, Masanori Hijioka, Xiaopeng Wen, Natsumi Iwashita, Junya Namba, Yoshiaki Nomura, Aoi Nakanishi, Soichiro Kitazawa, Ryo Honda, Yuji O Kamatari, Ryo Kitahara, Kenji Suzuki, Masatoshi Inden, Yoshihisa Kitamura.

  Synucleinopathies, including Parkinson's disease and dementia with Lewy bodies, are neurodegenerative disorders characterized by the aberrant accumulation of α-synuclein (α-syn). Although no treatment is effective for synucleinopathies, the suppression of α-syn aggregation may contribute to the development of numerous novel therapeutic targets. Recent research revealed that nicotinic acetylcholine (nACh) receptor activation has neuroprotective effects and promotes the degradation of amyloid protein by activating autophagy. In an in vitro human-derived cell line model, we demonstrated that galantamine, the nAChR allosteric potentiating ligand, significantly reduced the cell number of SH-SY5Y cells with intracellular Lewy body-like aggregates by enhancing the sensitivity of α7-nAChR. In addition, galantamine promoted autophagic flux, and prevented the formation of Lewy body-resembled aggregates. In an in vivo synucleinopathy mouse model, the propagation of α-syn aggregation in the cerebral cortex was inhibited by galantamine administration for 90 days. These results suggest that α7-nAChR is expected to be a novel therapeutic target, and galantamine is a potential agent for synucleinopathies.

Keywords:  Autophagy; Galantamine; Synucleinopathy; nACh receptors; α-syn aggregation

DOI:  https://doi.org/10.1016/j.jphs.2024.07.008
J Mol Biol. 2024 Aug 22. pii: S0022-2836(24)00360-7. [Epub ahead of print] 168751

Single acetylation-mimetic mutation in TDP-43 Nuclear Localization Signal disrupts importin α1/β signaling.

Ying-Hui Ko, Ravi K Lokareddy, Steven G Doll, Daniel P Yeggoni, Amandeep Girdhar, Ian Mawn, Joseph R Klim, Noreen F Rizvi, Rachel Meyers, Richard E Gillilan, Lin Guo, Gino Cingolani.

  Cytoplasmic aggregation of the TAR-DNA binding protein of 43 kDa (TDP-43) is the hallmark of sporadic amyotrophic lateral sclerosis (ALS). Most ALS patients with TDP-43 aggregates in neurons and glia do not have mutations in the TDP-43 gene but contain aberrantly post-translationally modified TDP-43. Here, we found that a single acetylation-mimetic mutation (K82Q) near the TDP-43 minor Nuclear Localization Signal (NLS) box, which mimics a post-translational modification identified in an ALS patient, can lead to TDP-43 mislocalization to the cytoplasm and irreversible aggregation. We demonstrate that the acetylation mimetic disrupts binding to importins, halting nuclear import and preventing importin α 1/ β anti-aggregation activity. We propose that perturbations near the NLS are an additional mechanism by which a cellular insult other than a genetically inherited mutation leads to TDP-43 aggregation and loss of function. Our findings are relevant to deciphering the molecular etiology of sporadic ALS.

Keywords:  ALS; TDP-43; acetylation; importin α 1; importin β; nuclear import; nuclear localization signal

DOI:  https://doi.org/10.1016/j.jmb.2024.168751
bioRxiv. 2024 Aug 17. pii: 2024.08.15.608042. [Epub ahead of print]

Quantitative 3D histochemistry reveals region-specific amyloid-β reduction by the antidiabetic drug netoglitazone.

Francesca Catto, Ehsan Dadgar-Kiani, Daniel Kirschenbaum, Athena E Economides, Anna Maria Reuss, Chiara Trevisan, Davide Caredio, Delic Mirzet, Lukas Frick, Ulrike Weber-Stadlbauer, Sergey Litvinov, Petros Koumoutsakos, Jin Hyung Lee, Adriano Aguzzi.

A hallmark of Alzheimer's disease (AD) is the extracellular aggregation of toxic amyloid-beta (Aβ) peptides in form of plaques. Here, we identify netoglitazone, an antidiabetic compound previously tested in humans, as an Aβ aggregation antagonist. Netoglitazone improved cognition and reduced microglia activity in a mouse model of AD. Using quantitative whole-brain three-dimensional histology (Q3D), we precisely identified brain regions where netoglitazone reduced the number and size of Aβ plaques. We demonstrate the utility of Q3D in preclinical drug evaluation for AD by providing a high-resolution brain-wide view of drug efficacy. Applying Q3D has the potential to improve pre-clinical drug evaluation by providing information that can help identify mechanisms leading to brain region-specific drug efficacy.

DOI: https://doi.org/10.1101/2024.08.15.608042
Int J Mol Sci. 2024 Aug 12. pii: 8779. [Epub ahead of print]25(16):

Phase Separation of SARS-CoV-2 Nucleocapsid Protein with TDP-43 Is Dependent on C-Terminus Domains.

Michael J Strong, Crystal McLellan, Brianna Kaplanis, Cristian A Droppelmann, Murray Junop.

  The SARS-CoV-2 nucleocapsid protein (N protein) is critical in viral replication by undergoing liquid-liquid phase separation to seed the formation of a ribonucleoprotein (RNP) complex to drive viral genomic RNA (gRNA) translation and in suppressing both stress granules and processing bodies, which is postulated to increase uncoated gRNA availability. The N protein can also form biomolecular condensates with a broad range of host endogenous proteins including RNA binding proteins (RBPs). Amongst these RBPs are proteins that are associated with pathological, neuronal, and glial cytoplasmic inclusions across several adult-onset neurodegenerative disorders, including TAR DNA binding protein 43 kDa (TDP-43) which forms pathological inclusions in over 95% of amyotrophic lateral sclerosis cases. In this study, we demonstrate that the N protein can form biomolecular condensates with TDP-43 and that this is dependent on the N protein C-terminus domain (N-CTD) and the intrinsically disordered C-terminus domain of TDP-43. This process is markedly accelerated in the presence of RNA. In silico modeling suggests that the biomolecular condensate that forms in the presence of RNA is composed of an N protein quadriplex in which the intrinsically disordered TDP-43 C terminus domain is incorporated.

Keywords:  RNA binding proteins; amyotrophic lateral sclerosis; biomolecular condensates; neurodegeneration; nucleocapsid protein

DOI:  https://doi.org/10.3390/ijms25168779
Front Mol Neurosci. 2024 ;17 1431079

Novel strategies in Parkinson's disease treatment: a review.

Charles L Mitchell, Dmitry Kurouski.

  An unprecedented extension of life expectancy observed during the past century drastically increased the number of patients diagnosed with Parkinson's diseases (PD) worldwide. Estimated costs of PD alone reached $52 billion per year, making effective neuroprotective treatments an urgent and unmet need. Current treatments of both AD and PD focus on mitigating the symptoms associated with these pathologies and are not neuroprotective. In this review, we discuss the most advanced therapeutic strategies that can be used to treat PD. We also critically review the shift of the therapeutic paradigm from a small molecule-based inhibition of protein aggregation to the utilization of natural degradation pathways and immune cells that are capable of degrading toxic amyloid deposits in the brain of PD patients.

Keywords:  Parkinson’s disease; amyloids; cell therapy; macrophages; natural kill cell

DOI:  https://doi.org/10.3389/fnmol.2024.1431079
Int J Mol Sci. 2024 Aug 15. pii: 8884. [Epub ahead of print]25(16):

Metformin Lysosomal Targeting: A Novel Aspect to Be Investigated for Metformin Repurposing in Neurodegenerative Diseases?

Nadia Papini, Paola Giussani, Cristina Tringali.

  Metformin is a widely employed drug in type 2 diabetes. In addition to warranting good short- and long-term glycemic control, metformin displays many intriguing properties as protection against cardiovascular and neurodegenerative diseases, anti-tumorigenic and longevity promotion. In addition to being a low-cost drug, metformin is generally well tolerated. However, despite the enthusiastic drive to aliment these novel studies, many contradictory results suggest the importance of better elucidating the complexity of metformin action in different tissues/cells to establish its possible employment in neurodegenerative diseases. This review summarises recent data identifying lysosomal-dependent processes and lysosomal targets, such as endosomal Na+/H+ exchangers, presenilin enhancer 2 (PEN2), the lysosomal pathway leading to AMP-activated protein kinase (AMPK) activation, and the transcription factor EB (TFEB), modulated by metformin. Lysosomal dysfunctions resulting in autophagic and lysosomal acidification and biogenesis impairment appear to be hallmarks of many inherited and acquired neurodegenerative diseases. Lysosomes are not yet seen as a sort of cellular dump but are crucial in determining key signalling paths and processes involved in the clearance of aggregated proteins. Thus, the possibility of pharmacologically modulating them deserves great interest. Despite the potentiality of metformin in this context, many additional important issues, such as dosing, should be addressed in the future.

Keywords:  lysosome; metformin; neurodegenerative diseases

DOI:  https://doi.org/10.3390/ijms25168884
Int J Mol Sci. 2024 Aug 16. pii: 8935. [Epub ahead of print]25(16):

Role of Lipids in the Pathogenesis of Parkinson's Disease.

Shumpei Kamano, Daisaku Ozawa, Kensuke Ikenaka, Yoshitaka Nagai.

  Aggregation of α-synuclein (αSyn) and its accumulation as Lewy bodies play a central role in the pathogenesis of Parkinson's disease (PD). However, the mechanism by which αSyn aggregates in the brain remains unclear. Biochemical studies have demonstrated that αSyn interacts with lipids, and these interactions affect the aggregation process of αSyn. Furthermore, genetic studies have identified mutations in lipid metabolism-associated genes such as glucocerebrosidase 1 (GBA1) and synaptojanin 1 (SYNJ1) in sporadic and familial forms of PD, respectively. In this review, we focus on the role of lipids in triggering αSyn aggregation in the pathogenesis of PD and propose the possibility of modulating the interaction of lipids with αSyn as a potential therapy for PD.

Keywords:  Parkinson’s disease; glucocerebrosidase; lipids; synaptojanin; α-synuclein

DOI:  https://doi.org/10.3390/ijms25168935
Medicine (Baltimore). 2024 Aug 23. 103(34): e39405

The mechanisms of Ca2+ regulating autophagy and its research progress in neurodegenerative diseases: A review.

Meng Hou, Zhixiao Zhang, Zexin Fan, Lei Huang, Li Wang.

Neurodegenerative diseases are complex disorders that significantly challenge human health, with their incidence increasing with age. A key pathological feature of these diseases is the accumulation of misfolded proteins. The underlying mechanisms involve an imbalance in calcium homeostasis and disturbances in autophagy, indicating a likely correlation between them. As the most important second messenger, Ca2+ plays a vital role in regulating various cell activities, including autophagy. Different organelles within cells serve as Ca2+ storage chambers and regulate Ca2+ levels under different conditions. Ca2+ in these compartments can affect autophagy via Ca2+ channels or other related signaling proteins. Researchers propose that Ca2+ regulates autophagy through distinct signal transduction mechanisms, under normal or stressful conditions, and thereby contributing to the occurrence and development of neurodegenerative diseases. This review provides a systematic examination of the regulatory mechanisms of Ca2+ in cell membranes and different organelles, as well as its downstream pathways that influence autophagy and its implications for neurodegenerative diseases. This comprehensive analysis may facilitate the development of new drugs and provide more precise treatments for neurodegenerative diseases.

DOI: https://doi.org/10.1097/MD.0000000000039405