bims-proned 2025-04-06 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2025–04–06
eight papers selected by
Verena Kohler, Umeå University

Cross-Interaction with Amyloid-β Drives Pathogenic Structural Transformation within the Amyloidogenic Core Region of TDP-43.
Alpha-Synuclein Phosphomimetic Y39E and S129D Knock-In Mice Show Cytosolic Alpha-Synuclein Localization without developing Neurodegeneration or Motor Deficits.
Caffeine and Nicotine with N-Substituted Diazirine Photoaffinity Labels Form Adducts at Tyrosine-39 of α-Synuclein.
Alpha-Synuclein Demonstrates Varying Binding Affinities With Different Tau Isoforms.
Factors Affecting Pathological Amyloid Protein Transformation: From Post-Translational Modifications to Chaperones.
iPAR: a new reporter for eukaryotic cytoplasmic protein aggregation.
α-Synuclein pathology and mitochondrial dysfunction: Toxic partners in Parkinson's disease.
Protein aggregation identified in olfactory neuronal cells is associated with cognitive impairments in a subset of living schizophrenia patients.

ACS Chem Neurosci. 2025 Apr 01.

Cross-Interaction with Amyloid-β Drives Pathogenic Structural Transformation within the Amyloidogenic Core Region of TDP-43.

Adam J Gatch, Feng Ding.

  Alzheimer's disease (AD) is the world's most prevalent neurodegenerative disorder, characterized neuropathologically by senile plaques and neurofibrillary tangles formed by amyloid-β (Aβ) and tau, respectively. Notably, a subset of AD patients also exhibits pathological aggregates composed of TAR DNA-Binding Protein 43 (TDP-43). Clinically, the presence of TDP-43 copathology in AD correlates with more severe cognitive decline and faster disease progression. While previous studies have shown that TDP-43 can exacerbate Aβ toxicity and modulate its assembly dynamics by delaying fibrillization and promoting oligomer formation, the impact of the Aβ interaction on the structural dynamics and aggregation of TDP-43 remains unclear. Here, we employed all-atom discrete molecular dynamics simulations to study the direct interaction between Aβ42, the more amyloidogenic isoform of Aβ, and the amyloidogenic core region (ACR) of TDP-43, which spans residues 311-360 and is critical for TDP-43 aggregation. We found that monomeric Aβ42 could strongly bind to the ACR, establishing sustained contact through intermolecular hydrogen bonding. In contrast, simulation of ACR dimerization revealed a transient helix-helix interaction, experimentally known to drive the phase separation behavior of TDP-43. The binding of the ACR to an Aβ42 fibril seed resulted in significant structural transformation, with the complete unfolding of the helical region being observed. Furthermore, interaction with the Aβ42 fibril seed catalyzed the formation of a parallel, in-register intermolecular β-sheet between two ACR monomers. Collectively, our computational study provides important theoretical insights into TDP-43 pathology in AD, demonstrating that Aβ42, especially in its fibrillar form, may catalyze the pathogenic structural transformation within the TDP-43 ACR that initiates its aberrant aggregation.

Keywords:  TDP-43; amyloid aggregation; amyloid-β; conformational dynamics; cross-interaction; cross-seeding

DOI:  https://doi.org/10.1021/acschemneuro.5c00084
eNeuro. 2025 Mar 31. pii: ENEURO.0357-24.2025. [Epub ahead of print]

Alpha-Synuclein Phosphomimetic Y39E and S129D Knock-In Mice Show Cytosolic Alpha-Synuclein Localization without developing Neurodegeneration or Motor Deficits.

YoungDoo Kim, Bhupesh Vaidya, Joseph McInnes, Huda Y Zoghbi.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms. Its pathological hallmarks include the accumulation of misfolded alpha-Synuclein (α-Syn) in Lewy bodies (LBs) and Lewy neurites. Phosphorylation of α-Syn is a prominent feature of these inclusions, but its role in disease pathogenesis remains unclear. To identify the role of α-Syn phosphorylation in Synucleinopathy, we generated two Snca knock-in (KI) mouse models carrying phosphomimetic mutations at SncaY39 or SncaS129 (SncaY39E or SncaS129D ) which manipulated epitopes phosphorylated in PD brain. Both SncaY39E and SncaS129D KI mice displayed increased α-Syn phosphorylation, enhanced oligomer formation, and a shift of α-Syn localization from membrane-bound to cytoplasm. However, neurodegeneration in substantia nigra was not observed up to 24 months of age. These findings demonstrate that mimicking the phosphorylation of Y39 or S129 can induce endogenous α-Syn phosphorylation. Still, a single phosphomimetic mutation alone is insufficient to induce PD-like behavior and pathology in the mouse's lifespan. Overall, our study provides a mouse model for investigating the role of phosphorylation at Y39 and S129 α-Syn epitopes in vivo.Significance statement Phosphorylation of specific α-Syn epitopes is observed in Parkinson's disease and other Lewy body diseases, but the direct relationship between phosphorylation at these sites and disease pathology remains unclear. This study focuses on two epitopes Y39 and S129, known to induce α-Syn protein aggregation in vitro, but in vivo data are either controversial (S129D) or missing (Y39E). We generated two phosphomimetic mutant (SncaY39E and SncaS129D ) KI mice that show shifting of α-Syn localization from the membrane to the cytosol, and enhancement of protein oligomerization, highlighting a potential role of these α-Syn phosphorylation sites in the initial steps of protein aggregation.

DOI: https://doi.org/10.1523/ENEURO.0357-24.2025
ACS Chem Neurosci. 2025 Apr 01.

Caffeine and Nicotine with N-Substituted Diazirine Photoaffinity Labels Form Adducts at Tyrosine-39 of α-Synuclein.

Melissa Mejia-Gutierrez, Brigitte Moser, Marissa Pirlot, Haixia Zhang, Paulos Chumala, George S Katselis, David R J Palmer, Ed S Krol.

  Aggregates of the protein α-synuclein are found in Lewy bodies in the brains of Parkinson's disease (PD) patients. Small molecules that can attenuate or halt α-synuclein aggregation have been studied as potential therapeutics for PD. However, we have a limited understanding of how these molecules bind to α-synuclein. We previously identified that caffeine, nicotine, and 1-aminoindan all bind to both the N- and C-terminus of α-synuclein, although the binding location remains unknown. In an effort to identify these binding regions on α-synuclein, we synthesized diazirine photoaffinity probes attached to caffeine (C-Dz), nicotine (N-Dz), and 1-aminoindan (I-Dz) and allowed each to react with α-synuclein in vitro. We then treated the incubation mixture with trypsin and employed time-of-flight mass spectrometry to analyze the resulting peptides. Our findings reveal a distinctive binding pattern among the probes: C-Dz forms covalent bonds with Tyr-39 and Glu-20, while N-Dz selectively forms a covalent bond with Tyr-39. Intriguingly, we could not detect the labeling of I-Dz to any specific amino acids. All of the diazirine-bound peptides were found near the N-terminus. Our results suggest that the N-terminal region near Tyr-39 bears further study to elucidate the binding interactions of small molecules with α-synuclein and may be a target for anti-PD agents.

Keywords:  caffeine; diazirine; nicotine; photoaffinity labeling; synucleinopathies; α-synuclein

DOI:  https://doi.org/10.1021/acschemneuro.5c00074
J Neurochem. 2025 Apr;169(4): e70053

Alpha-Synuclein Demonstrates Varying Binding Affinities With Different Tau Isoforms.

Anna-Lisa Fischer, Matthias Schmitz, Tobias Thom, Saima Zafar, Neelam Younas, Susana da Silva Correia, Angela da Silva Correia, Sezgi Canaslan Eyyuboglu, Inga Zerr.

  The hallmark of various neurodegenerative diseases is the accumulation and aggregation of amyloidogenic proteins, such as amyloid-beta (Aβ) and tau in Alzheimer's disease (AD) and alpha-synuclein (aSyn) in synucleinopathies. Many neurodegenerative diseases express mixed pathology. For instance, Lewy bodies are reported in tauopathies and neurofibrillary tau-tangles are detected in synucleinopathies, suggesting a potential co-existence or crosstalk of misfolded aSyn and tau. In the present study, we investigated the binding characteristics of monomeric aSyn with different tau isoforms by using surface plasmon resonance (SPR) spectroscopy allowing monitoring direct protein-protein interactions and their potential co-localization using SH-SY5Y cells. The calculation of the binding parameters (association and dissociation rate constants) indicated the strongest binding affinity between aSyn and tau isoform 1N3R followed by tau 2N3R and tau 2N4R. Co-localization studies in SH-SY5Y cells, treated with aSyn and all six tau isoforms revealed an intracellular co-localization of aSyn with different isoforms of tau. Subcellular fractionation confirmed the cellular uptake and colocalization of tau and aSyn in the same compartment, showing their expression in membrane, nuclear, and cytoskeletal fractions. Understanding the intricate interplay between aSyn and tau is crucial for unraveling the pathophysiology of PD, AD, and related neurodegenerative disorders, ultimately paving the way for the development of effective treatments targeting this interaction. In conclusion, our data indicate that aSyn and tau are direct interaction partners with varying binding affinities depending on the tau isoform. This interaction may be significant for understanding the pathophysiology of dementia with mixed pathologies.

Keywords:  Alzheimer's disease; Parkinson's disease; alpha‐synuclein; interaction; synucleinopathies; tau; tauopathies

DOI:  https://doi.org/10.1111/jnc.70053
Biochemistry (Mosc). 2025 Jan;90(Suppl 1): S164-S192

Factors Affecting Pathological Amyloid Protein Transformation: From Post-Translational Modifications to Chaperones.

Vladimir I Muronets, Sofiya S Kudryavtseva, Lidia P Kurochkina, Evgeniia V Leisi, Yulia Yu Stroylova, Elena V Schmalhausen.

  The review discusses the influence of various factors (e.g., post-translational modifications and chaperones) on the pathological transformation of amyloidogenic proteins involved in the onset and development of neurodegenerative diseases (Alzheimer's and Parkinson's diseases) and spongiform encephalopathies of various origin with special focus on the role of α-synuclein, prion protein, and, to a lesser extent, beta-amyloid peptide. The factors investigated by the authors of this review are discussed in more detail, including posttranslational modifications (glycation and S-nitrosylation), cinnamic acid derivatives and dendrimers, and chaperonins (eukaryotic, bacterial, and phage). A special section is devoted to the role of the gastrointestinal microbiota in the pathogenesis of amyloid neurodegenerative diseases, in particular, its involvement in the transformation of infectious prions and possibly other proteins capable of prion-like transmission of amyloidogenic diseases.

Keywords:  chaperons; microbiota; post-translational modifications; prion protein; α-synuclein; β-amyloid

DOI:  https://doi.org/10.1134/S0006297924604003
BMC Methods. 2025 ;2(1): 5

iPAR: a new reporter for eukaryotic cytoplasmic protein aggregation.

Sarah Lecinski, Jamieson A L Howard, Chris MacDonald, Mark C Leake.

   Background: Cells employ myriad regulatory mechanisms to maintain protein homeostasis, termed proteostasis, to ensure correct cellular function. Dysregulation of proteostasis, which is often induced by physiological stress and ageing, often results in protein aggregation in cells. These aggregated structures can perturb normal physiological function, compromising cell integrity and viability, a prime example being early onset of several neurodegenerative diseases. Understanding aggregate dynamics in vivo is therefore of strong interest for biomedicine and pharmacology. However, factors involved in formation, distribution and clearance of intracellular aggregates are not fully understood.
Methods: Here, we report an improved methodology for production of fluorescent aggregates in model budding yeast which can be detected, tracked and quantified using fluorescence microscopy in live cells. This new openly-available technology, iPAR (inducible Protein Aggregation Reporter), involves monomeric fluorescent protein reporters fused to a ∆ssCPY* aggregation biomarker, with expression controlled under the copper-regulated CUP1 promoter.
Results: Monomeric tags overcome challenges associated with non-physiological reporter aggregation, whilst CUP1 provides more precise control of protein production. We show that iPAR and the associated bioimaging methodology enables quantitative study of cytoplasmic aggregate kinetics and inheritance features in vivo. We demonstrate that iPAR can be used with traditional epifluorescence and confocal microscopy as well as single-molecule precise Slimfield millisecond microscopy. Our results indicate that cytoplasmic aggregates are mobile and contain a broad range of number of iPAR molecules, from tens to several hundred per aggregate, whose mean value increases with extracellular hyperosmotic stress.
Discussion: Time lapse imaging shows that although larger iPAR aggregates associate with nuclear and vacuolar compartments, we show directly, for the first time, that these proteotoxic accumulations are not inherited by daughter cells, unlike nuclei and vacuoles. If suitably adapted, iPAR offers new potential for studying diseases relating to protein oligomerization processes in other model cellular systems.
Supplementary Information: The online version contains supplementary material available at 10.1186/s44330-025-00023-w.

Keywords:  Cell ageing; Confocal microscopy; Inheritance; Protein aggregation; Saccharomyces cerevisiae; Single-molecule

DOI:  https://doi.org/10.1186/s44330-025-00023-w
Neurobiol Dis. 2025 Mar 27. pii: S0969-9961(25)00105-6. [Epub ahead of print]209 106889

α-Synuclein pathology and mitochondrial dysfunction: Toxic partners in Parkinson's disease.

Yakum B Mingo, Martha L Escobar Galvis, Michael X Henderson.

  Two major neuropathological features of Parkinson's disease (PD) are α-synuclein Lewy pathology and mitochondrial dysfunction. Although both α-synuclein pathology and mitochondrial dysfunction may independently contribute to PD pathogenesis, the interaction between these two factors is not yet fully understood. In this review, we discuss the physiological functions of α-synuclein and mitochondrial homeostasis in neurons as well as the pathological defects that ensue when these functions are disturbed in PD. Recent studies have highlighted that dysfunctional mitochondria can become sequestered within Lewy bodies, and cell biology studies have suggested that α-synuclein can directly impair mitochondrial function. There are also PD cases caused by genetic or environmental perturbation of mitochondrial homeostasis. Together, these studies suggest that mitochondrial dysfunction may be a common pathway to neurodegeneration in PD, triggered by multiple insults. We review the literature surrounding the interaction between α-synuclein and mitochondria and highlight open questions in the field that may be explored to advance our understanding of PD and develop novel, disease-modifying therapies.

Keywords:  Cell death; Mitochondrial complex I; PINK1; Parkin; mtDNA; α-Synuclein

DOI:  https://doi.org/10.1016/j.nbd.2025.106889
Mol Psychiatry. 2025 Apr 03.

Protein aggregation identified in olfactory neuronal cells is associated with cognitive impairments in a subset of living schizophrenia patients.

Leslie G Nucifora, Koko Ishizuka, Nagat El Demerdash, Brian J Lee, Michael T Imai, Carlos Ayala-Grosso, Gayane Yenokyan, Nicola G Cascella, Sandra Lin, David J Schretlen, Philip D Harvey, Russell L Margolis, Christopher A Ross, Akira Sawa, Frederick C Nucifora.

Schizophrenia is a heterogeneous disorder, and likely results from multiple pathophysiological mechanisms. Protein aggregation, resulting from disruption of protein homeostasis (proteostasis), has been implicated in many diseases, including cancer, cardiac and pulmonary diseases, muscle diseases, and neurodegenerative disorders, but is a relatively new pathophysiological hypothesis for schizophrenia. Genetic findings implicate proteostasis in schizophrenia, and individual proteins associated with the disorder may undergo aggregation. While there is some evidence of associations between genetic variants and protein aggregation, the extent to which genetic variations influence protein aggregation remains unknown. We have previously reported increased protein insolubility and increased ubiquitination of the insoluble protein fraction, two markers of protein aggregation, in human postmortem brains from a subset of patients with schizophrenia. In the present study, we investigate whether protein aggregation is observed in an independent model system, olfactory neuronal cells derived from living patients with schizophrenia, and examine the relationship between aggregation and patient clinical and cognitive status. We demonstrate that, as in postmortem brain, olfactory neurons from a subset of patients with schizophrenia exhibit protein aggregation, identified by increased protein insolubility and ubiquitination of the insoluble protein fraction, and by ubiquitin positive protein aggregates. Patients with protein aggregation exhibit more severe cognitive deficits than those without aggregation, as revealed by between-group comparisons and correlational analyses. Understanding the mechanisms of the aggregation process, the factors that differentiate individuals who develop aggregates from those who do not, and the relationship between aggregation and cell function, has important implications for the pathophysiology of schizophrenia, and may provide insight into disease heterogeneity and novel therapeutic targets.

DOI: https://doi.org/10.1038/s41380-025-02956-8