bims-proned 2024-08-04 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2024–08–04
twelve papers selected by
Verena Kohler, Umeå University

The antiviral drug Ribavirin effectively modulates the amyloid transformation of α-Synuclein protein.
O-GlcNAc Modification of α-Synuclein Can Alter Monomer Dynamics to Control Aggregation Kinetics.
Modulation of α-synuclein aggregation amid diverse environmental perturbation.
TDP-43 proteinopathy in frontotemporal lobar degeneration and amyotrophic lateral sclerosis: From pathomechanisms to therapeutic strategies.
Cholesterol imbalance and neurotransmission defects in neurodegeneration.
Molecular signatures of neurodegenerative diseases identified by proteomic and phosphoproteomic analyses in aging mouse brain.
Bifurcations in coupled amyloid-β aggregation-inflammation systems.
Energetic portrait of the amyloid beta nucleation transition state.
TDP-43 Promotes Amyloid-Beta Toxicity by Delaying Fibril Maturation via Direct Molecular Interaction.
tRNA Arg binds in vitro TDP-43 RNA recognition motifs and ligand of Ate1 protein LIAT1.
Amyloid fibril structures link CHCHD10 and CHCHD2 to neurodegeneration.
Advances in Ubiquitination and Proteostasis in Retinal Degeneration.

Comput Biol Chem. 2024 Jul 16. pii: S1476-9271(24)00143-9. [Epub ahead of print]112 108155

The antiviral drug Ribavirin effectively modulates the amyloid transformation of α-Synuclein protein.

Payal Singh, Almas Akhtar, Nikita Admane, Abhinav Grover.

  α-Synuclein (α-syn) is an intrinsically disordered protein, linked genetically and neuropathologically to Parkinson's disease where this protein aggregates within the brain. Hence, identifying compounds capable of impeding α-syn aggregation puts forward a promising approach for the development of disease-modifying therapies. Herein, we investigated the efficacy of Ribavirin, an FDA-approved compound, in curtailing α-syn amyloid transformation, employing an array of bioinformatic tools and systematic analysis using biophysical techniques. Ribavirin shows a dose dependent anti-aggregation propensity where it effectively subdued the formation of mature fibrillar aggregates of α-syn, where even at the lowest concentration there was a 69 % reduction in the ThT maxima. Ribavirin averts the formation of mature fibrillar aggregates by interacting with the NAC domain of α-syn. Ribavirin redirects the amyloid transformation of α-syn by emanating aggregates of lower order with reduced cross β-sheet signature and revokes the formation of on-pathway amyloids. Collectively, our study puts forward the novel potency of Ribavirin as a promising molecule for therapeutic intervention in Parkinson's disease.

Keywords:  Biophysical assay; Molecular docking; Parkinson disease; REMD simulation; Ribavirin; α-Synuclein

DOI:  https://doi.org/10.1016/j.compbiolchem.2024.108155
ACS Chem Neurosci. 2024 Jul 31.

O-GlcNAc Modification of α-Synuclein Can Alter Monomer Dynamics to Control Aggregation Kinetics.

Kasun Gamage, Binyou Wang, Eldon R Hard, Thong Van, Ana Galesic, George R Phillips, Matthew Pratt, Lisa J Lapidus.

  The intrinsically disordered protein α-Synuclein is identified as a major toxic aggregate in Parkinson's as well as several other neurodegenerative diseases. Recent work on this protein has focused on the effects of posttranslational modifications on aggregation kinetics. Among them, O-GlcNAcylation of α-Synuclein has been observed to inhibit the aggregation propensity of the protein. Here, we investigate the monomer dynamics of two O-GlcNAcylated α-Synucleins, α-Syn(gT72), and α-Syn(gS87) and correlate them with the aggregation kinetics. We find that, compared to the unmodified protein, glycosylation at T72 makes the protein less compact and more diffusive, while glycosylation at S87 makes the protein more compact and less diffusive. Based on a model of the earliest steps in aggregation, we predict that T72 should aggregate slower than unmodified protein, which is confirmed by ThT fluorescence measurements. In contrast, S87 should aggregate faster, which is not mirrored in ThT kinetics of later fibril formation but does not rule out a higher rate of formation of small oligomers. Together, these results show that posttranslational modifications do not uniformly affect aggregation propensity.

Keywords:  Parkinson’s disease; aggregation; glycosylation; intramolecular diffusion; posttranslational modification; α-Synuclein

DOI:  https://doi.org/10.1021/acschemneuro.4c00301
Elife. 2024 Aug 01. pii: RP95180. [Epub ahead of print]13

Modulation of α-synuclein aggregation amid diverse environmental perturbation.

Abdul Wasim, Sneha Menon, Jagannath Mondal.

  Intrinsically disordered protein α-synuclein (αS) is implicated in Parkinson's disease due to its aberrant aggregation propensity. In a bid to identify the traits of its aggregation, here we computationally simulate the multi-chain association process of αS in aqueous as well as under diverse environmental perturbations. In particular, the aggregation of αS in aqueous and varied environmental condition led to marked concentration differences within protein aggregates, resembling liquid-liquid phase separation (LLPS). Both saline and crowded settings enhanced the LLPS propensity. However, the surface tension of αS droplet responds differently to crowders (entropy-driven) and salt (enthalpy-driven). Conformational analysis reveals that the IDP chains would adopt extended conformations within aggregates and would maintain mutually perpendicular orientations to minimize inter-chain electrostatic repulsions. The droplet stability is found to stem from a diminished intra-chain interactions in the C-terminal regions of αS, fostering inter-chain residue-residue interactions. Intriguingly, a graph theory analysis identifies small-world-like networks within droplets across environmental conditions, suggesting the prevalence of a consensus interaction patterns among the chains. Together these findings suggest a delicate balance between molecular grammar and environment-dependent nuanced aggregation behavior of αS.

Keywords:  LLPS; coarse-grained MD simulation; crowding; human; molecular biophysics; salt; structural biology

DOI:  https://doi.org/10.7554/eLife.95180
Ageing Res Rev. 2024 Jul 27. pii: S1568-1637(24)00259-9. [Epub ahead of print]100 102441

TDP-43 proteinopathy in frontotemporal lobar degeneration and amyotrophic lateral sclerosis: From pathomechanisms to therapeutic strategies.

Pei-Chuan Ho, Tsung-Chi Hsieh, Kuen-Jer Tsai.

  Proteostasis failure is a common pathological characteristic in neurodegenerative diseases. Revitalizing clearance systems could effectively mitigate these diseases. The transactivation response (TAR) DNA-binding protein 43 (TDP-43) plays a critical role as an RNA/DNA-binding protein in RNA metabolism and synaptic function. Accumulation of TDP-43 aggregates in the central nervous system is a hallmark of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Autophagy, a major and highly conserved degradation pathway, holds the potential for degrading aggregated TDP-43 and alleviating FTLD/ALS. This review explores the causes of TDP-43 aggregation, FTLD/ALS-related genes, key autophagy factors, and autophagy-based therapeutic strategies targeting TDP-43 proteinopathy. Understanding the underlying pathological mechanisms of TDP-43 proteinopathy can facilitate therapeutic interventions.

Keywords:  Amyotrophic lateral sclerosis; Autophagy; Frontotemporal lobar degeneration; TDP-43

DOI:  https://doi.org/10.1016/j.arr.2024.102441
Exp Mol Med. 2024 Aug 01.

Cholesterol imbalance and neurotransmission defects in neurodegeneration.

Kyung Chul Shin, Houda Yasmine Ali Moussa, Yongsoo Park.

The brain contains the highest concentration of cholesterol in the human body, which emphasizes the importance of cholesterol in brain physiology. Cholesterol is involved in neurogenesis and synaptogenesis, and age-related reductions in cholesterol levels can lead to synaptic loss and impaired synaptic plasticity, which potentially contribute to neurodegeneration. The maintenance of cholesterol homeostasis in the neuronal plasma membrane is essential for normal brain function, and imbalances in cholesterol distribution are associated with various neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and Huntington's disease. This review aims to explore the molecular and pathological mechanisms by which cholesterol imbalance can lead to neurotransmission defects and neurodegeneration, focusing on four key mechanisms: (1) synaptic dysfunction, (2) alterations in membrane structure and protein clustering, (3) oligomers of amyloid beta (Aβ) protein, and (4) α-synuclein aggregation.

DOI: https://doi.org/10.1038/s12276-024-01273-4
Mol Cell Proteomics. 2024 Jul 26. pii: S1535-9476(24)00109-9. [Epub ahead of print] 100819

Molecular signatures of neurodegenerative diseases identified by proteomic and phosphoproteomic analyses in aging mouse brain.

Rodrigo Mohallem, Allison Schaser, Uma K Aryal.

A central hallmark of neurodegenerative diseases is the irreversible accumulation of misfolded proteins in the brain by aberrant phosphorylation. Understanding the mechanisms underlying protein phosphorylation and its role in pathological protein aggregation within the context of aging is crucial for developing therapeutic strategies aimed at preventing or reversing such diseases. Here, we applied multi-protease digestion and quantitative mass spectrometry to compare and characterize dysregulated proteins and phosphosites in the mouse brain proteome using three different age groups: young-adult (3-4 months), middle-age (10 months), and old mice (19-21 months). Proteins associated with senescence, neurodegeneration, inflammation, cell cycle regulation, the p53 hallmark pathway, and cytokine signaling showed significant age-dependent changes in abundances and level of phosphorylation. Several proteins implicated in Alzheimer's and Parkinson's diseases including tau (Mapt), Nefh, and Dpysl2 (also known as Crmp2) were hyperphosphorylated in old mice brain suggesting their susceptibility to the diseases. Cdk5 and Gsk3b, which are known to phosphorylate Dpysl2 at multiple specific sites, had also increased phosphorylation levels in old mice suggesting a potential crosstalk between them to contribute to AD. Hapln2, which promotes α-synuclein aggregation in patients with PD, was one of the proteins with highest abundance in old mice. CD9, which regulates senescence through the PI3K-AKT-mTOR-p53 signaling was upregulated in old mice and its regulation was correlated with the activation of phosphorylated AKT1. Overall, the findings identify a significant association between aging and the dysregulation of proteins involved in various pathways linked to neurodegenerative diseases with potential therapeutic implications.

DOI: https://doi.org/10.1016/j.mcpro.2024.100819
NPJ Syst Biol Appl. 2024 Jul 30. 10(1): 80

Bifurcations in coupled amyloid-β aggregation-inflammation systems.

Kalyan S Chakrabarti, Davood Bakhtiari, Nasrollah Rezaei-Ghaleh.

A complex interplay between various processes underlies the neuropathology of Alzheimer's disease (AD) and its progressive course. Several lines of evidence point to the coupling between Aβ aggregation and neuroinflammation and its role in maintaining brain homeostasis during the long prodromal phase of AD. Little is however known about how this protective mechanism fails and as a result, an irreversible and progressive transition to clinical AD occurs. Here, we introduce a minimal model of a coupled system of Aβ aggregation and inflammation, numerically simulate its dynamical behavior, and analyze its bifurcation properties. The introduced model represents the following events: generation of Aβ monomers, aggregation of Aβ monomers into oligomers and fibrils, induction of inflammation by Aβ aggregates, and clearance of various Aβ species. Crucially, the rates of Aβ generation and clearance are modulated by inflammation level following a Hill-type response function. Despite its relative simplicity, the model exhibits enormously rich dynamics ranging from overdamped kinetics to sustained oscillations. We then specify the region of inflammation- and coupling-related parameters space where a transition to oscillatory dynamics occurs and demonstrate how changes in Aβ aggregation parameters could shift this oscillatory region in parameter space. Our results reveal the propensity of coupled Aβ aggregation-inflammation systems to oscillatory dynamics and propose prolonged sustained oscillations and their consequent immune system exhaustion as a potential mechanism underlying the transition to a more progressive phase of amyloid pathology in AD. The implications of our results in regard to early diagnosis of AD and anti-AD drug development are discussed.

DOI: https://doi.org/10.1038/s41540-024-00408-7
bioRxiv. 2024 Jul 24. pii: 2024.07.24.604935. [Epub ahead of print]

Energetic portrait of the amyloid beta nucleation transition state.

Anna Arutyunyan, Mireia Seuma, Andre J Faure, Benedetta Bolognesi, Ben Lehner.

Amyloid protein aggregates are pathological hallmarks of more than fifty human diseases including the most common neurodegenerative disorders. The atomic structures of amyloid fibrils have now been determined, but the process by which soluble proteins nucleate to form amyloids remains poorly characterised and difficult to study, even though this is the key step to understand to prevent the formation and spread of aggregates. Here we use massively parallel combinatorial mutagenesis, a kinetic selection assay, and machine learning to reveal the transition state of the nucleation reaction of amyloid beta, the protein that aggregates in Alzheimer's disease. By quantifying the nucleation of >140,000 proteins we infer the changes in activation energy for all 798 amino acid substitutions in amyloid beta and the energetic couplings between >600 pairs of mutations. This unprecedented dataset provides the first comprehensive view of the energy landscape and the first large-scale measurement of energetic couplings for a protein transition state. The energy landscape reveals that the amyloid beta nucleation transition state contains a short structured C-terminal hydrophobic core with a subset of interactions similar to mature fibrils. This study demonstrates the feasibility of using mutation-selection-sequencing experiments to study transition states and identifies the key molecular species that initiates amyloid beta aggregation and, potentially, Alzheimer's disease.

DOI: https://doi.org/10.1101/2024.07.24.604935
ACS Chem Neurosci. 2024 Jul 29.

TDP-43 Promotes Amyloid-Beta Toxicity by Delaying Fibril Maturation via Direct Molecular Interaction.

Adam J Gatch, Feng Ding.

  Amyloid-β (Aβ) is a peptide that undergoes self-assembly into amyloid fibrils, which compose the hallmark plaques observed in Alzheimer's disease (AD). TAR DNA-binding protein 43 (TDP-43) is a protein with mislocalization and aggregation implicated in amyotrophic lateral sclerosis and other neurodegenerative diseases. Recent work suggests that TDP-43 may interact with Aβ, inhibiting the formation of amyloid fibrils and worsening AD pathology, but the molecular details of their interaction remain unknown. Using all-atom discrete molecular dynamics simulations, we systematically investigated the direct molecular interaction between Aβ and TDP-43. We found that Aβ monomers were able to bind near the flexible nuclear localization sequence of the N-terminal domain (NTD) of TDP-43, adopting β-sheet rich conformations that were promoted by the interaction. Furthermore, Aβ associated with the nucleic acid binding interface of the tandem RNA recognition motifs of TDP-43 via electrostatic interactions. Using the computational peptide array method, we found the strongest C-terminal domain interaction with Aβ to be within the amyloidogenic core region of TDP-43. With experimental evidence suggesting that the NTD is necessary for inhibiting Aβ fibril growth, we also simulated the NTD with an Aβ40 fibril seed. We found that the NTD was able to strongly bind the elongation surface of the fibril seed via extensive hydrogen bonding and could also diffuse along the lateral surface via electrostatic interactions. Our results suggest that TDP-43 binding to the elongation surface, thereby sterically blocking Aβ monomer addition, is responsible for the experimentally observed inhibition of fibril growth. We conclude that TDP-43 may promote Aβ toxicity by stabilizing the oligomeric state and kinetically delaying fibril maturation.

Keywords:  Alzheimer’s disease; TDP-43; amyloid aggregation; amyloid-β; cross-interaction; cross-seeding

DOI:  https://doi.org/10.1021/acschemneuro.4c00334
MicroPubl Biol. 2024 ;2024

tRNA Arg binds in vitro TDP-43 RNA recognition motifs and ligand of Ate1 protein LIAT1.

Ljiljana Sjekloća, Emanuele Buratti.

Transactive response DNA-binding protein 43 (TDP-43) is important for RNA metabolism in all animals and its malfunctions are linked to neurodegenerative and myodegenerative diseases in humans. Arginyl transferase Ate1 transfers an arginyl group from arginylated tRNA Arg to proteolytic fragments of the C-terminal region of TDP-43, prompting their degradation by the ubiquitin proteasome system, thus contributing to TDP-43 proteostasis. To gain more insight into the molecular basis of TDP-43 arginylation, we tested if tRNA Arg could bind in vitro to a panel of recombinant multidomain constructs of human TDP-43 or to the arginylation cofactor protein LIAT1. We observed that in vitro- transcribed human tRNA Arg directly interacts with the RNA recognition motifs of TDP-43 and that their binding is stabilized by dimerization, which is promoted by the amino-terminal domain and the nuclear localization signal sequence of TDP-43. Moreover, the same human TDP-43 constructs that bind tRNA Arg bind native fungal tRNA Phe , suggesting that TDP-43 can bind different populations of tRNAs. Interestingly, human tRNA Arg is also able to bind recombinant mouse LIAT1 suggesting, for the first time, that LIAT1 is an RNA-binding protein. Our findings open a new perspective on the intricate crosstalk between protein and tRNA metabolism, which may eventually contribute to the understanding of the role of TDP-43 proteostasis in health and disease.

DOI: https://doi.org/10.17912/micropub.biology.001224
bioRxiv. 2024 Jul 22. pii: 2024.07.18.604174. [Epub ahead of print]

Amyloid fibril structures link CHCHD10 and CHCHD2 to neurodegeneration.

Guohua Lv, Nicole M Sayles, Yun Huang, Chiara D Mancinelli, Kevin McAvoy, Neil A Shneider, Giovanni Manfredi, Hibiki Kawamata, David Eliezer.

CHCHD10 is mutated in rare cases of FTD and ALS and aggregates in mouse models of disease. Here we show that the disordered N-terminal domain of CHCHD10 forms amyloid fibrils and report their cryoEM structure. Disease-associated mutations cannot be accommodated by the WT fibril structure, while sequence differences between CHCHD10 and CHCHD2 are tolerated, explaining the co-aggregation of the two proteins and linking CHCHD10 and CHCHD2 amyloid fibrils to neurodegeneration.

DOI: https://doi.org/10.1101/2024.07.18.604174
Front Biosci (Landmark Ed). 2024 Jul 22. 29(7): 260

Advances in Ubiquitination and Proteostasis in Retinal Degeneration.

Jia Wei, Xiaona Chen, Yingyue Xiong, Yali Gao.

  Retinal degeneration (RD) is a group of chronic blinding diseases characterised by progressive retinal cell death. As the disease progresses, vision deteriorates due to retinal cell death and impaired retinal integrity, eventually leading to complete loss of vision. Therefore, the function and environmental homeostasis of the retina have an important impact on the pathogenesis and treatment of RD. Ubiquitination, as a complex post-translational modification process, plays an essential role in maintaining retinal homeostasis and normal function. It covalently combines ubiquitin with protein through a series of enzyme-mediated reactions, and participates in cell processes such as gene transcription, cell cycle process, DNA repair, apoptosis and immune response. At the same time, it plays a central role in protein degradation. There are two major protein degradation systems in eukaryotic cells: the ubiquitin-proteasome system and the autophagy-lysosomal system. The protein degradation pathway maintains retinal protein homeostasis by reducing abnormal protein accumulation in the retina through two modes of degradation. Either dysregulation of ubiquitination or disruption of protein homeostasis may lead to the development of RD. This article aims to comprehensively review recent research progress on ubiquitin-related genes, proteins and protein homeostasis in the pathogenesis of RD, and to summarize the potential targeted therapy strategies for it. The review is expected to provide valuable guidance for further development and application of ubiquitination in RD.

Keywords:  autophagy; retinal degeneration; ubiquitin-proteasome system; ubiquitination

DOI:  https://doi.org/10.31083/j.fbl2907260