bims-proned 2024-07-14 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2024–07–14
fourteen papers selected by
Verena Kohler, Umeå University

20S proteasome enhancers prevent cytotoxic tubulin polymerization-promoting protein induced α-synuclein aggregation.
S100A9 inhibits and redirects prion protein 89-230 fragment amyloid aggregation.
Specific inhibition of α-synuclein oligomer generation and toxicity by the chaperone domain Bri2 BRICHOS.
Transcellular transmission and molecular heterogeneity of aggregation-prone proteins in neurodegenerative diseases.
Phase Separation and Aggregation of α-Synuclein Diverge at Different Salt Conditions.
DNA Damage and Chromatin Rearrangement Work Together to Promote Neurodegeneration.
Excitatory synaptic structural abnormalities produced by templated aggregation of α-syn in the basolateral amygdala.
A peptide strategy for inhibiting different protein aggregation pathways.
α-Linolenic Acid Vesicles-Mediated Tau Internalization in Microglia.
Gut-Brain Axis in Focus: Polyphenols, Microbiota, and Their Influence on α-Synuclein in Parkinson's Disease.
Oligodendrocyte Dysfunction in Tauopathy: A Less Explored Area in Tau-Mediated Neurodegeneration.
High frequency electrical stimulation reduces α-synuclein levels and α-synuclein-mediated autophagy dysfunction.
Alpha-Synuclein Interaction with UBL3 Is Upregulated by Microsomal Glutathione S-Transferase 3, Leading to Increased Extracellular Transport of the Alpha-Synuclein under Oxidative Stress.
Preparation and Characterization of Zn(II)-Stabilized Aβ42 Oligomers.

iScience. 2024 Jul 19. 27(7): 110166

20S proteasome enhancers prevent cytotoxic tubulin polymerization-promoting protein induced α-synuclein aggregation.

Sophia D Staerz, Charles Anamoah, Jetze J Tepe.

  Synucleinopathies are a class of neurodegenerative diseases defined by the presence of α-synuclein inclusions. The location and composition of these α-synuclein inclusions directly correlate to the disease pattern. The inclusions in Multiple System Atrophy are located predominantly in oligodendrocytes and are rich in a second protein, p25α. P25α plays a key role in neuronal myelination by oligodendrocytes. In healthy oligodendrocytes, there is little to no α-synuclein present. If aberrant α-synuclein is present, p25α leaves the myelin sheaths and quickly co-aggregates with α-synuclein, resulting in the disruption of the cellular process and ultimately cell death. Herein, we report that p25α is susceptible for 20S proteasome-mediated degradation and that p25α induces α-synuclein aggregation, resulting in proteasome impairment and cell death. In addition, we identified small molecules 20S proteasome enhancers that prevent p25α induced α-synuclein fibrilization, restore proteasome impairment, and enhance cell viability.

Keywords:  cell biology; cellular neuroscience; pathophysiology

DOI:  https://doi.org/10.1016/j.isci.2024.110166
Arch Biochem Biophys. 2024 Jul 06. pii: S0003-9861(24)00209-1. [Epub ahead of print]758 110087

S100A9 inhibits and redirects prion protein 89-230 fragment amyloid aggregation.

Mantas Ziaunys, Darius Sulskis, Kamile Mikalauskaite, Andrius Sakalauskas, Ruta Snieckute, Vytautas Smirnovas.

  Protein aggregation in the form of amyloid fibrils has long been associated with the onset and development of various amyloidoses, including Alzheimer's, Parkinson's or prion diseases. Recent studies of their fibril formation process have revealed that amyloidogenic protein cross-interactions may impact aggregation pathways and kinetic parameters, as well as the structure of the resulting aggregates. Despite a growing number of reports exploring this type of interaction, they only cover just a small number of possible amyloidogenic protein pairings. One such pair is between two neurodegeneration-associated proteins: the pro-inflammatory S100A9 and prion protein, which are known to co-localize in vivo. In this study, we examined their cross-interaction in vitro and discovered that the fibrillar form of S100A9 modulated the aggregation pathway of mouse prion protein 89-230 fragment, while non-aggregated S100A9 also significantly inhibited its primary nucleation process. These results complement previous observations of the pro-inflammatory protein's role in amyloid aggregation and highlight its potential role against neurodegenerative disorders.

Keywords:  Cross-interaction; Prion protein; S100A9

DOI:  https://doi.org/10.1016/j.abb.2024.110087
Protein Sci. 2024 Aug;33(8): e5091

Specific inhibition of α-synuclein oligomer generation and toxicity by the chaperone domain Bri2 BRICHOS.

Laurène Adam, Rakesh Kumar, Luis Enrique Arroyo-Garcia, Willem Hendrik Molenkamp, Jan Stanislaw Nowak, Hannah Klute, Azad Farzadfard, Rami Alkenayeh, Janni Nielsen, Henrik Biverstål, Daniel E Otzen, Jan Johansson, Axel Abelein.

  Protein misfolding and aggregation are involved in several neurodegenerative disorders, such as α-synuclein (αSyn) implicated in Parkinson's disease, where new therapeutic approaches remain essential to combat these devastating diseases. Elucidating the microscopic nucleation mechanisms has opened new opportunities to develop therapeutics against toxic mechanisms and species. Here, we show that naturally occurring molecular chaperones, represented by the anti-amyloid Bri2 BRICHOS domain, can be used to target αSyn-associated nucleation processes and structural species related to neurotoxicity. Our findings revealed that BRICHOS predominantly suppresses the formation of new nucleation units on the fibrils surface (secondary nucleation), decreasing the oligomer generation rate. Further, BRICHOS directly binds to oligomeric αSyn species and effectively diminishes αSyn fibril-related toxicity. Hence, our studies show that molecular chaperones can be utilized as tools to target molecular processes and structural species related to αSyn neurotoxicity and have the potential as protein-based treatments against neurodegenerative disorders.

Keywords:  BRICHOS domain; molecular chaperone; protein aggregation; α‐Synuclein

DOI:  https://doi.org/10.1002/pro.5091
Mol Cells. 2024 Jul 04. pii: S1016-8478(24)00114-6. [Epub ahead of print] 100089

Transcellular transmission and molecular heterogeneity of aggregation-prone proteins in neurodegenerative diseases.

Eunmin Lee, Hyeonwoo Park, Sangjune Kim.

  The accumulation of aggregation-prone proteins in a specific neuronal population is a common feature of neurodegenerative diseases, which is correlated with the development of pathological lesions in diseased brains. The formation and progression of pathological protein aggregates in susceptible neurons induce cellular dysfunction, resulting in progressive degeneration. Moreover, recent evidence supports the notion that the cell-to-cell transmission of pathological protein aggregates may be involved in the onset and progression of many neurodegenerative diseases. Indeed, several studies have identified different pathological aggregate strains. Although how these different aggregate strains form remains unclear, a variety of biomolecular compositions or cross-seeding events promoted by the presence of other protein aggregates in the cellular environment may affect the formation of different strains of pathological aggregates, which in turn can influence complex pathologies in diseased brains. In this review, we summarize the recent results regarding cell-to-cell transmission and the molecular heterogeneity of pathological aggregate strains, raising key questions for future research directions.

Keywords:  Cell-to-cell transmission; Different strains; Neurodegenerative diseases; Protein aggregates; Selective vulnerability

DOI:  https://doi.org/10.1016/j.mocell.2024.100089
Adv Sci (Weinh). 2024 Jul 07. e2308279

Phase Separation and Aggregation of α-Synuclein Diverge at Different Salt Conditions.

Rebecca Sternke-Hoffmann, Xun Sun, Andreas Menzel, Miriam Dos Santos Pinto, Urte Venclovaite, Michael Wördehoff, Wolfgang Hoyer, Wenwei Zheng, Jinghui Luo.

  The coacervation of alpha-synuclein (αSyn) into cytotoxic oligomers and amyloid fibrils are considered pathological hallmarks of Parkinson's disease. While aggregation is central to amyloid diseases, liquid-liquid phase separation (LLPS) and its interplay with aggregation have gained increasing interest. Previous work shows that factors promoting or inhibiting aggregation have similar effects on LLPS. This study provides a detailed scanning of a wide range of parameters, including protein, salt and crowding concentrations at multiple pH values, revealing different salt dependencies of aggregation and LLPS. The influence of salt on aggregation under crowding conditions follows a non-monotonic pattern, showing increased effects at medium salt concentrations. This behavior can be elucidated through a combination of electrostatic screening and salting-out effects on the intramolecular interactions between the N-terminal and C-terminal regions of αSyn. By contrast, this study finds a monotonic salt dependence of LLPS due to intermolecular interactions. Furthermore, it observes time evolution of the two distinct assembly states, with macroscopic fibrillar-like bundles initially forming at medium salt concentration but subsequently converting into droplets after prolonged incubation. The droplet state is therefore capable of inhibiting aggregation or even dissolving aggregates through heterotypic interactions, thus preventing αSyn from its dynamically arrested state.

Keywords:  aggregation; biomolecular condensates; intrinsically disordered proteins; liquid–liquid phase separation; molecular dynamics

DOI:  https://doi.org/10.1002/advs.202308279
Mol Neurobiol. 2024 Jul 08.

DNA Damage and Chromatin Rearrangement Work Together to Promote Neurodegeneration.

Harman Sharma, Sushma Koirala, Yee Lian Chew, Anna Konopka.

  Neurodegenerative diseases have a complex origin and are composed of genetic and environmental factors. Both DNA damage and chromatin rearrangement are important processes that occur under pathological conditions and in neurons functioning properly. While numerous studies have demonstrated the inseparable relationship between DNA damage and chromatin organization, understanding of this relationship, especially in neurodegenerative diseases, requires further study. Interestingly, recent studies revealed that known hallmark proteins involved in neurodegenerative diseases function in both DNA damage and chromatin reorganization, and this review discusses the current knowledge of this relationship. This review focused on hallmark proteins involved in various neurodegenerative diseases, such as the microtubule-associated protein tau, TAR DNA/RNA binding protein 43 (TDP-43), superoxide dismutase 1 (SOD1), fused in sarcoma (FUS), huntingtin (HTT), α-synuclein, and β-amyloid precursor protein (APP). Hence, DNA damage and chromatin rearrangement are associated with disease mechanisms in distinct neurodegenerative diseases. Targeting common modulators of DNA repair and chromatin reorganization may lead to promising therapies for treating neurodegeneration.

Keywords:  Chromatin rearrangement; DNA damage; Hallmark proteins; Neurodegeneration

DOI:  https://doi.org/10.1007/s12035-024-04331-0
Neurobiol Dis. 2024 Jul 06. pii: S0969-9961(24)00195-5. [Epub ahead of print]199 106595

Excitatory synaptic structural abnormalities produced by templated aggregation of α-syn in the basolateral amygdala.

Nolwazi Z Gcwensa, Dreson L Russell, Khaliah Y Long, Charlotte F Brzozowski, Xinran Liu, Karen L Gamble, Rita M Cowell, Laura A Volpicelli-Daley.

  Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) are characterized by neuronal α-synuclein (α-syn) inclusions termed Lewy Pathology, which are abundant in the amygdala. The basolateral amygdala (BLA), in particular, receives projections from the thalamus and cortex. These projections play a role in cognition and emotional processing, behaviors which are impaired in α-synucleinopathies. To understand if and how pathologic α-syn impacts the BLA requires animal models of α-syn aggregation. Injection of α-syn pre-formed fibrils (PFFs) into the striatum induces robust α-syn aggregation in excitatory neurons in the BLA that corresponds with reduced contextual fear conditioning. At early time points after aggregate formation, cortico-amygdala excitatory transmission is abolished. The goal of this project was to determine if α-syn inclusions in the BLA induce synaptic degeneration and/or morphological changes. In this study, we used C57BL/6 J mice injected bilaterally with PFFs in the dorsal striatum to induce α-syn aggregate formation in the BLA. A method was developed using immunofluorescence and three-dimensional reconstruction to analyze excitatory cortico-amygdala and thalamo-amygdala presynaptic terminals closely juxtaposed to postsynaptic densities. The abundance and morphology of synapses were analyzed at 6- or 12-weeks post-injection of PFFs. α-Syn aggregate formation in the BLA did not cause a significant loss of synapses, but cortico-amygdala and thalamo-amygdala presynaptic terminals and postsynaptic densities with aggregates of α-syn show increased volumes, similar to previous findings in human DLB cortex, and in non-human primate models of PD. Transmission electron microscopy showed that asymmetric synapses in mice with PFF-induced α-syn aggregates have reduced synaptic vesicle intervesicular distances, similar to a recent study showing phospho-serine-129 α-syn increases synaptic vesicle clustering. Thus, pathologic α-syn causes major alterations to synaptic architecture in the BLA, potentially contributing to behavioral impairment and amygdala dysfunction observed in synucleinopathies.

Keywords:  Basolateral amygdala; Dementia with Lewy bodies; Glutamatergic; P-α-syn; Parkinson's disease; Presynaptic terminal; Synapses

DOI:  https://doi.org/10.1016/j.nbd.2024.106595
Chemistry. 2024 Jul 07. e202400080

A peptide strategy for inhibiting different protein aggregation pathways.

Tommaso Garfagnini, Luca Ferrari, Margreet B Koopman, Francoise A Dekker, Sem Halters, Eline Van Kappel, Guy Mayer, Shachar Bressler, Madelon M Maurice, Stefan G D Rudiger, Assaf Friedler.

  Protein aggregation correlates with many human diseases. Protein aggregates differ in structure and shape. Strategies to develop effective aggregation inhibitors that reach the clinic failed so far. Here, we developed a family of peptides targeting early aggregation stages for both amorphous and fibrillar aggregates of proteins unrelated in sequence and structure. They act on dynamic precursors before mechanistic differentiation takes place. Using peptide arrays, we first identified peptides inhibiting the amorphous aggregation of a molten globular, aggregation-prone mutant of the Axin tumor suppressor. Optimization revealed that the peptides activity did not depend on their sequences but rather on their molecular determinants: a composition of 20-30% flexible, 30-40% aliphatic and 20-30% aromatic residues, a hydrophobicity/hydrophilicity ratio close to 1, and an even distribution of residues of different nature throughout the sequence. The peptides also suppressed fibrillation of Tau, a disordered protein that forms amyloids in Alzheimer's disease, and slowed down that of Huntingtin Exon1, an amyloidogenic protein in Huntington's disease, both entirely unrelated to Axin. Our compounds thus target early aggregation stages of different aggregation mechanisms, inhibiting both amorphous and amyloid aggregation. Such cross-mechanistic, multi-targeting aggregation inhibitors may be lead compounds for developing drug candidates against various protein aggregation diseases.

Keywords:  amyloid fibrils; peptide arrays; peptide design; protein aggregation inhibition; tau

DOI:  https://doi.org/10.1002/chem.202400080
Methods Mol Biol. 2024 ;2816 117-128

α-Linolenic Acid Vesicles-Mediated Tau Internalization in Microglia.

Subashchandrabose Chinnathambi.

  In Alzheimer's disease, the synaptic loss is prominent due to the accumulation of Amyloid βeta (Aβ) protein in synapses, which affect neurotransmission, and thus ultimately causes neuronal loss. Tau, a microtubule-associated protein, is a vital protein of intracellular neurofibrillary tangles (NFTs) in AD. Along with the accumulation of aberrant proteins, glial cells, mainly astrocytes and microglia, play a major role in impairing neuronal network. Microglia have the ability to phagocytose Tau and rerelease in exosomes, which causes further spreading of Tau. Reduction in exosome synthesis can reduce spreading of Tau. Modulating microglia to clear the extracellular Tau seeds by its imported degradation would resolve the disease condition in Alzheimer's disease. In this study, we have shown the ability of α-linolenic acid (ALA) to inhibit the Tau aggregation and modulate their internalization property in microglial cells.

Keywords:  Extracellualr Tau; Tau internalization; Tau microglia; α-Linolenic acid

DOI:  https://doi.org/10.1007/978-1-0716-3902-3_11
Nutrients. 2024 Jun 27. pii: 2041. [Epub ahead of print]16(13):

Gut-Brain Axis in Focus: Polyphenols, Microbiota, and Their Influence on α-Synuclein in Parkinson's Disease.

Elizabeth Riegelman, Kathy S Xue, Jia-Sheng Wang, Lili Tang.

  With the recognition of the importance of the gut-brain axis in Parkinson's disease (PD) etiology, there is increased interest in developing therapeutic strategies that target α-synuclein, the hallmark abhorrent protein of PD pathogenesis, which may originate in the gut. Research has demonstrated that inhibiting the aggregation, oligomerization, and fibrillation of α-synuclein are key strategies for disease modification. Polyphenols, which are rich in fruits and vegetables, are drawing attention for their potential role in this context. In this paper, we reviewed how polyphenols influence the composition and functional capabilities of the gut microbiota and how the resulting microbial metabolites of polyphenols may potentially enhance the modulation of α-synuclein aggregation. Understanding the interaction between polyphenols and gut microbiota and identifying which specific microbes may enhance the efficacy of polyphenols is crucial for developing therapeutic strategies and precision nutrition based on the microbiome.

Keywords:  Parkinsons’s disease; gut microbiota; gut–brain axis; polyphenols; α-synuclein

DOI:  https://doi.org/10.3390/nu16132041
Cells. 2024 Jun 27. pii: 1112. [Epub ahead of print]13(13):

Oligodendrocyte Dysfunction in Tauopathy: A Less Explored Area in Tau-Mediated Neurodegeneration.

Moumita Majumder, Debashis Dutta.

  Aggregation of the microtubule-associated protein tau (MAPT) is the hallmark pathology in a spectrum of neurodegenerative disorders collectively called tauopathies. Physiologically, tau is an inherent neuronal protein that plays an important role in the assembly of microtubules and axonal transport. However, disease-associated mutations of this protein reduce its binding to the microtubule components and promote self-aggregation, leading to formation of tangles in neurons. Tau is also expressed in oligodendrocytes, where it has significant developmental roles in oligodendrocyte maturation and myelin synthesis. Oligodendrocyte-specific tau pathology, in the form of fibrils and coiled coils, is evident in major tauopathies including progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick's disease (PiD). Multiple animal models of tauopathy expressing mutant forms of MAPT recapitulate oligodendroglial tau inclusions with potential to cause degeneration/malfunction of oligodendrocytes and affecting the neuronal myelin sheath. Till now, mechanistic studies heavily concentrated on elucidating neuronal tau pathology. Therefore, more investigations are warranted to comprehensively address tau-induced pathologies in oligodendrocytes. The present review provides the current knowledge available in the literature about the intricate relations between tau and oligodendrocytes in health and diseases.

Keywords:  MAPT; myelin; neurodegeneration; oligodendrocytes; tauopathy

DOI:  https://doi.org/10.3390/cells13131112
Sci Rep. 2024 Jul 12. 14(1): 16091

High frequency electrical stimulation reduces α-synuclein levels and α-synuclein-mediated autophagy dysfunction.

Jimmy George, Kashfia Shafiq, Minesh Kapadia, Lorraine V Kalia, Suneil K Kalia.

  Accumulation of α-synuclein (α-Syn) has been implicated in proteasome and autophagy dysfunction in Parkinson's disease (PD). High frequency electrical stimulation (HFS) mimicking clinical parameters used for deep brain stimulation (DBS) in vitro or DBS in vivo in preclinical models of PD have been found to reduce levels of α-Syn and, in certain cases, provide possible neuroprotection. However, the mechanisms by which this reduction in α-Syn improves cellular dysfunction associated with α-Syn accumulation remains elusive. Using HFS parameters that recapitulate DBS in vitro, we found that HFS led to a reduction of mutant α-Syn and thereby limited proteasome and autophagy impairments due to α-Syn. Additionally, we observed that HFS modulates via the ATP6V0C subunit of V-ATPase and mitigates α-Syn mediated autophagic dysfunction. This study highlights a role for autophagy in reduction of α-Syn due to HFS which may prove to be a viable approach to decrease pathological protein accumulation in neurodegeneration.

Keywords:  ATPases; Alpha-synuclein; Autophagy; Deep brain stimulation; High frequency stimulation; Parkinson’s disease

DOI:  https://doi.org/10.1038/s41598-024-64131-3
Int J Mol Sci. 2024 Jul 04. pii: 7353. [Epub ahead of print]25(13):

Alpha-Synuclein Interaction with UBL3 Is Upregulated by Microsomal Glutathione S-Transferase 3, Leading to Increased Extracellular Transport of the Alpha-Synuclein under Oxidative Stress.

Jing Yan, Tomoaki Kahyo, Hengsen Zhang, Yashuang Ping, Chi Zhang, Shuyun Jiang, Qianqing Ji, Rafia Ferdous, Md Shoriful Islam, Soho Oyama, Shuhei Aramaki, Tomohito Sato, Mst Afsana Mimi, Md Mahmudul Hasan, Mitsutoshi Setou.

  Aberrant aggregation of misfolded alpha-synuclein (α-syn), a major pathological hallmark of related neurodegenerative diseases such as Parkinson's disease (PD), can translocate between cells. Ubiquitin-like 3 (UBL3) is a membrane-anchored ubiquitin-fold protein and post-translational modifier. UBL3 promotes protein sorting into small extracellular vesicles (sEVs) and thereby mediates intercellular communication. Our recent studies have shown that α-syn interacts with UBL3 and that this interaction is downregulated after silencing microsomal glutathione S-transferase 3 (MGST3). However, how MGST3 regulates the interaction of α-syn and UBL3 remains unclear. In the present study, we further explored this by overexpressing MGST3. In the split Gaussia luciferase complementation assay, we found that the interaction between α-syn and UBL3 was upregulated by MGST3. While Western blot and RT-qPCR analyses showed that silencing or overexpression of MGST3 did not significantly alter the expression of α-syn and UBL3, the immunocytochemical staining analysis indicated that MGST3 increased the co-localization of α-syn and UBL3. We suggested roles for the anti-oxidative stress function of MGST3 and found that the effect of MGST3 overexpression on the interaction between α-syn with UBL3 was significantly rescued under excess oxidative stress and promoted intracellular α-syn to extracellular transport. In conclusion, our results demonstrate that MGST3 upregulates the interaction between α-syn with UBL3 and promotes the interaction to translocate intracellular α-syn to the extracellular. Overall, our findings provide new insights and ideas for promoting the modulation of UBL3 as a therapeutic agent for the treatment of synucleinopathy-associated neurodegenerative diseases.

Keywords:  alpha-synuclein; microsomal glutathione s-transferase 3; neuroprotection; oxidative stress; small extracellular vesicles; synucleinopathy; ubiquitin-like 3

DOI:  https://doi.org/10.3390/ijms25137353
ACS Chem Neurosci. 2024 Jul 09.

Preparation and Characterization of Zn(II)-Stabilized Aβ42 Oligomers.

Alicia González Díaz, Rodrigo Cataldi, Benedetta Mannini, Michele Vendruscolo.

  Aβ oligomers are being investigated as cytotoxic agents in Alzheimer's disease (AD). Because of their transient nature and conformational heterogeneity, the relationship between the structure and activity of these oligomers is still poorly understood. Hence, methods for stabilizing Aβ oligomeric species relevant to AD are needed to uncover the structural determinants of their cytotoxicity. Here, we build on the observation that metal ions and metabolites have been shown to interact with Aβ, influencing its aggregation and stabilizing its oligomeric species. We thus developed a method that uses zinc ions, Zn(II), to stabilize oligomers produced by the 42-residue form of Aβ (Aβ42), which is dysregulated in AD. These Aβ42-Zn(II) oligomers are small in size, spanning the 10-30 nm range, stable at physiological temperature, and with a broad toxic profile in human neuroblastoma cells. These oligomers offer a tool to study the mechanisms of toxicity of Aβ oligomers in cellular and animal AD models.

Keywords:  Alzheimer′s disease; Aβ42; neurodegeneration; oligomers; zinc

DOI:  https://doi.org/10.1021/acschemneuro.4c00084