bims-proned 2024-05-05 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2024‒05‒05
thirteen papers selected by
Verena Kohler, Umeå University

Exploring Structural Insights of Aβ42 and α-Synuclein Monomers and Heterodimer: A Comparative Study Using Implicit and Explicit Solvent Simulations.
The role of age-associated alpha-synuclein aggregation in a conditional transgenic mouse model of Parkinson's disease: Implications for Lewy body formation.
Parkinson's Disease-associated mutations in α-synuclein alters its lipid-bound state.
Interplay between α-synuclein and parkin genes: Insights of Parkinson's disease.
Insight into the Effect of Methylglyoxal on the Conformation, Function, and Aggregation Propensity of α-Synuclein.
A Targetable N-Terminal Motif Orchestrates α-Synuclein Oligomer-to-Fibril Conversion.
Polymeric Nanozyme with SOD Activity Capable of Inhibiting Self- and Metal-Induced α-Synuclein Aggregation.
Probing protein aggregation through spectroscopic insights and multimodal approaches: A comprehensive review for counteracting neurodegenerative disorders.
Protein mimetic 2D FAST rescues alpha synuclein aggregation mediated early and post disease Parkinson's phenotypes.
CK1δ/ε kinases regulate TDP-43 phosphorylation and are therapeutic targets for ALS-related TDP-43 hyperphosphorylation.
Actin-nucleation promoting factor N-WASP influences alpha-synuclein condensates and pathology.
Misfolded protein deposits in Parkinson's disease and Parkinson's disease-related cognitive impairment, a [11C]PBB3 study.
Age-dependent dynamics of neuronal VAPBALS inclusions in the adult brain.

J Phys Chem B. 2024 May 03.

Exploring Structural Insights of Aβ42 and α-Synuclein Monomers and Heterodimer: A Comparative Study Using Implicit and Explicit Solvent Simulations.

Yuliia Varenyk, Panagiotis E Theodorakis, Dinh Q H Pham, Mai Suan Li, Paweł Krupa.

Protein misfolding, aggregation, and fibril formation play a central role in the development of severe neurological disorders, including Alzheimer's and Parkinson's diseases. The structural stability of mature fibrils in these diseases is of great importance, as organisms struggle to effectively eliminate amyloid plaques. To address this issue, it is crucial to investigate the early stages of fibril formation when monomers aggregate into small, toxic, and soluble oligomers. However, these structures are inherently disordered, making them challenging to study through experimental approaches. Recently, it has been shown experimentally that amyloid-β 42 (Aβ42) and α-synuclein (α-Syn) can coassemble. This has motivated us to investigate the interaction between their monomers as a first step toward exploring the possibility of forming heterodimeric complexes. In particular, our study involves the utilization of various Amber and CHARMM force-fields, employing both implicit and explicit solvent models in replica exchange and conventional simulation modes. This comprehensive approach allowed us to assess the strengths and weaknesses of these solvent models and force fields in comparison to experimental and theoretical findings, ensuring the highest level of robustness. Our investigations revealed that Aβ42 and α-Syn monomers can indeed form stable heterodimers, and the resulting heterodimeric model exhibits stronger interactions compared to the Aβ42 dimer. The binding of α-Syn to Aβ42 reduces the propensity of Aβ42 to adopt fibril-prone conformations and induces significant changes in its conformational properties. Notably, in AMBER-FB15 and CHARMM36m force fields with the use of explicit solvent, the presence of Aβ42 significantly increases the β-content of α-Syn, consistent with the experiments showing that Aβ42 triggers α-Syn aggregation. Our analysis clearly shows that although the use of implicit solvent resulted in too large compactness of monomeric α-Syn, structural properties of monomeric Aβ42 and the heterodimer were preserved in explicit-solvent simulations. We anticipate that our study sheds light on the interaction between α-Syn and Aβ42 proteins, thus providing the atom-level model required to assess the initial stage of aggregation mechanisms related to Alzheimer's and Parkinson's diseases.

DOI: https://doi.org/10.1021/acs.jpcb.4c00503
J Neurochem. 2024 May 01.

The role of age-associated alpha-synuclein aggregation in a conditional transgenic mouse model of Parkinson's disease: Implications for Lewy body formation.

Jiahua Li, Ka Wai Ng, Chun Chau Sung, Kenny K K Chung.

  Parkinson's disease (PD) is a common neurodegenerative disorder that is affecting an increasing number of older adults. Although PD is mostly sporadic, genetic mutations have been found in cohorts of families with a history of familial PD (FPD). The first such mutation linked to FPD causes a point mutation (A53T) in α-synuclein (α-syn), a major component of Lewy bodies, which are a classical pathological hallmark of PD. These findings suggest that α-syn is an important contributor to the development of PD. In our previous study, we developed an adenoviral mouse model of PD and showed that the expression of wild-type (WT) α-syn or a mutant form with an increased propensity to aggregate, designated as WT-CL1 α-syn, could be used to study how α-syn aggregation contributes to PD. In this study, we established a transgenic mouse model that conditionally expresses WT or WT-CL1 α-syn in dopaminergic (DA) neurons and found that the expression of either WT or WT-CL1 α-syn was associated with an age-dependent degeneration of DA neurons and movement dysfunction. Using this model, we were able to monitor the process of α-syn aggregate formation and found a correlation between age and the number and sizes of α-syn aggregates formed. These results provide a potential mechanism by which age-dependent α-syn aggregation may lead to the formation of Lewy bodies in PD pathogenesis.

Keywords:  Lewy body; Parkinson's disease; aging; alpha‐synuclein

DOI:  https://doi.org/10.1111/jnc.16122
Biophys J. 2024 May 02. pii: S0006-3495(24)00316-3. [Epub ahead of print]

Parkinson's Disease-associated mutations in α-synuclein alters its lipid-bound state.

Sofiya Maltseva, Daniel Kerr, Miah Turke, Erin J Adams, Ka Yee C Lee.

Lipid binding properties of α-synuclein play a central role in protein aggregation and progression of Parkinson's Disease (PD). α-Synuclein, an intrinsically disordered protein, binds to lipid membranes through the formation of two amphipathic helices that insert into the lipid bilayer. All disease-associated single point mutations have been identified to be within these helical regions of α-synuclein: V15A, A30P, E46K, H50Q, G51D, A53T, and A53V. However, the effects of these mutations on the bound states of the two α-helices of the protein have yet to be fully characterized. In this report, we use a tryptophan fluorescence assay to measure the binding of the α-helices of these PD-associated mutants to lipid membranes within the lipid depletion regime. We characterize the binding behavior of each helix, revealing that generally, the PD-associated mutants shift the equilibrium bound state away from the N-terminal helix of the protein toward Helix 2 at lower lipid concentrations. Altogether, our results indicate that disruption to the equilibrium binding of the two α-helices of α-synuclein could play a role in PD progression.

DOI: https://doi.org/10.1016/j.bpj.2024.05.002
Mol Biol Rep. 2024 Apr 29. 51(1): 586

Interplay between α-synuclein and parkin genes: Insights of Parkinson's disease.

Kajal Sharma, Shivani Chib, Aniket Gupta, Randhir Singh, Rishabh Chalotra.

  Parkinson's disease (PD) is a complex and debilitating neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra. The pathogenesis of PD is intimately linked to the roles of two key molecular players, α-synuclein (α-syn) and Parkin. Understanding the intricate interplay between α-syn and Parkin is essential for unravelling the molecular underpinnings of PD. Their roles in synaptic function and protein quality control underscore their significance in neuronal health. Dysregulation of these processes, as seen in PD, highlights the potential for targeted therapeutic strategies aimed at restoring normal protein homeostasis and mitigating neurodegeneration. Investigating the connections between α-syn, Parkin, and various pathological mechanisms provides insights into the complex web of factors contributing to PD pathogenesis and offers hope for the development of more effective treatments for this devastating neurological disorder. The present compilation provides an overview of their structures, regional and cellular locations, associations, physiological functions, and pathological roles in the context of PD.

Keywords:  Neurodegeneration; Parkin; Parkinson’s disease; α-synuclein

DOI:  https://doi.org/10.1007/s11033-024-09520-7
Chemistry. 2024 Apr 30. e202400890

Insight into the Effect of Methylglyoxal on the Conformation, Function, and Aggregation Propensity of α-Synuclein.

Laura Mariño, Ana Belén Uceda, Francisco Leal, Miquel Adrover.

  It is well-known that people suffering from hyperglycemia have a higher propensity to develop Parkinson's disease (PD). One of the most plausible mechanisms linking these two pathologies is the glycation of neuronal proteins and the pathological consequences of it. α-Synuclein, a key component in PD, can be glycated at its fifteen lysine. In fact, the end products of this process have been detected on aggregated α-synuclein isolated from in vivo. However, the consequences of glycation are not entirely clear, which are of crucial importance to understand the mechanism underlying the connection between diabetes and PD. To better clarify this, we have here examined how methylglyoxal (the most important carbonyl compound found in the cytoplasm) affects the conformation and aggregation propensity of α-synuclein, as well as its ability to cluster and fuse synaptic-like vesicles. The obtained data prove that methylglyoxal induces the Lys-Lys crosslinking through the formation of MOLD. However, this does not have a remarkable effect on the averaged conformational ensemble of α-synuclein, although it completely depletes its native propensity to form soluble oligomers and insoluble amyloid fibrils. Moreover, methylglyoxal has a disrupting effect on the ability of α-synuclein to bind, cluster and fusion synaptic-like vesicles.

Keywords:  Human α-synuclein Synaptic vesicles Aggregation Protein glycation Methylglyoxal

DOI:  https://doi.org/10.1002/chem.202400890
J Am Chem Soc. 2024 Apr 29.

A Targetable N-Terminal Motif Orchestrates α-Synuclein Oligomer-to-Fibril Conversion.

Jaime Santos, Jorge Cuellar, Irantzu Pallarès, Emily J Byrd, Alons Lends, Fernando Moro, Muhammed Bilal Abdul-Shukkoor, Jordi Pujols, Lorea Velasco-Carneros, Frank Sobott, Daniel E Otzen, Antonio N Calabrese, Arturo Muga, Jan Skov Pedersen, Antoine Loquet, Jose María Valpuesta, Sheena E Radford, Salvador Ventura.

Oligomeric species populated during α-synuclein aggregation are considered key drivers of neurodegeneration in Parkinson's disease. However, the development of oligomer-targeting therapeutics is constrained by our limited knowledge of their structure and the molecular determinants driving their conversion to fibrils. Phenol-soluble modulin α3 (PSMα3) is a nanomolar peptide binder of α-synuclein oligomers that inhibits aggregation by blocking oligomer-to-fibril conversion. Here, we investigate the binding of PSMα3 to α-synuclein oligomers to discover the mechanistic basis of this protective activity. We find that PSMα3 selectively targets an α-synuclein N-terminal motif (residues 36-61) that populates a distinct conformation in the mono- and oligomeric states. This α-synuclein region plays a pivotal role in oligomer-to-fibril conversion as its absence renders the central NAC domain insufficient to prompt this structural transition. The hereditary mutation G51D, associated with early onset Parkinson's disease, causes a conformational fluctuation in this region, leading to delayed oligomer-to-fibril conversion and an accumulation of oligomers that are resistant to remodeling by molecular chaperones. Overall, our findings unveil a new targetable region in α-synuclein oligomers, advance our comprehension of oligomer-to-amyloid fibril conversion, and reveal a new facet of α-synuclein pathogenic mutations.

DOI: https://doi.org/10.1021/jacs.4c02262
Chemistry. 2024 Apr 30. e202401331

Polymeric Nanozyme with SOD Activity Capable of Inhibiting Self- and Metal-Induced α-Synuclein Aggregation.

Álvaro Martínez-Camarena, Francesco Bellia, M Paz Clares, Graziella Vecchio, Julien Nicolas, Enrique García-España.

  Despite decades of research, Parkinson's disease is still an idiopathic pathology for which no cure has yet been found. This is partly explained by the multifactorial character of most neurodegenerative syndromes, whose generation involves multiple pathogenic factors. Two of the most important ones are the aggregation of α-synuclein and oxidative stress. In this work, we address both issues by synthesizing a multifunctional nanozyme based on grafting a pyridinophane ligand that can strongly coordinate CuII, onto biodegradable PEGylated polyester nanoparticles. The resulting nanozyme exhibits remarkable superoxide dismutase activity together with the ability to inhibit the self-induced aggregation of α-synuclein into amyloid-type fibrils. Furthermore, the combination of the chelator and the polymer produces a cooperative effect whereby the resulting nanozyme can also halve CuII-induced α-synuclein aggregation.

Keywords:  Nanozyme; Polymers; aggregation; superoxide dismutase activity; α-synuclein

DOI:  https://doi.org/10.1002/chem.202401331
Heliyon. 2024 Apr 15. 10(7): e27949

Probing protein aggregation through spectroscopic insights and multimodal approaches: A comprehensive review for counteracting neurodegenerative disorders.

Sania Bashir, Ayesha Aiman, Anis Ahmad Chaudhary, Nashrah Khan, Ishfaq Ahmad Ahanger, Neha Sami, Eman Abdullah Almugri, Mohamed A M Ali, Salah-Ud-Din Khan, Mohammad Shahid, Seemi Farhat Basir, Md Imtaiyaz Hassan, Asimul Islam.

  Aberrant accumulation of protein misfolding can cause aggregation and fibrillation and is one of the primary characteristic features of neurodegenerative diseases. Because they are disordered, misfolded, and aggregated proteins pose a significant setback in drug designing. The structural study of intermediate steps in these kinds of aggregated proteins will allow us to determine the conformational changes as well as the probable pathways encompassing various neurodegenerative disorders. The analysis of protein aggregates involved in neurodegenerative diseases relies on a diverse toolkit of biophysical techniques, encompassing both morphological and non-morphological methods. Additionally, Thioflavin T (ThT) assays and Circular Dichroism (CD) spectroscopy facilitate investigations into aggregation kinetics and secondary structure alterations. The collective application of these biophysical techniques empowers researchers to comprehensively unravel the intricate nature of protein aggregates associated with neurodegeneration. Furthermore, the topics covered in this review have summed up a handful of well-established techniques used for the structural analysis of protein aggregation. This multifaceted approach advances our fundamental understanding of the underlying mechanisms driving neurodegenerative diseases and informs potential therapeutic strategies.

Keywords:  Neurodegenerative diseases; Protein aggregation; Structural analysis

DOI:  https://doi.org/10.1016/j.heliyon.2024.e27949
Nat Commun. 2024 Apr 30. 15(1): 3658

Protein mimetic 2D FAST rescues alpha synuclein aggregation mediated early and post disease Parkinson's phenotypes.

Nicholas H Stillman, Johnson A Joseph, Jemil Ahmed, Charles Zuwu Baysah, Ryan A Dohoney, Tyler D Ball, Alexandra G Thomas, Tessa C Fitch, Courtney M Donnelly, Sunil Kumar.

Abberent protein-protein interactions potentiate many diseases and one example is the toxic, self-assembly of α-Synuclein in the dopaminergic neurons of patients with Parkinson's disease; therefore, a potential therapeutic strategy is the small molecule modulation of α-Synuclein aggregation. In this work, we develop an Oligopyridylamide based 2-dimensional Fragment-Assisted Structure-based Technique to identify antagonists of α-Synuclein aggregation. The technique utilizes a fragment-based screening of an extensive array of non-proteinogenic side chains in Oligopyridylamides, leading to the identification of NS132 as an antagonist of the multiple facets of α-Synuclein aggregation. We further identify a more cell permeable analog (NS163) without sacrificing activity. Oligopyridylamides rescue α-Synuclein aggregation mediated Parkinson's disease phenotypes in dopaminergic neurons in early and post disease Caenorhabditis elegans models. We forsee tremendous potential in our technique to identify lead therapeutics for Parkinson's disease and other diseases as it is expandable to other oligoamide scaffolds and a larger array of side chains.

DOI: https://doi.org/10.1038/s41467-024-47980-4
Neurobiol Dis. 2024 Apr 25. pii: S0969-9961(24)00115-3. [Epub ahead of print]196 106516

CK1δ/ε kinases regulate TDP-43 phosphorylation and are therapeutic targets for ALS-related TDP-43 hyperphosphorylation.

Vivian I Ko, Kailee Ong, Don W Cleveland, Haiyang Yu, John M Ravits.

  Hyperphosphorylated TAR DNA-binding protein 43 (TDP-43) aggregates in the cytoplasm of neurons is the neuropathological hallmark of amyotrophic lateral sclerosis (ALS) and a group of neurodegenerative diseases collectively referred to as TDP-43 proteinopathies that includes frontotemporal dementia, Alzheimer's disease, and limbic onset age-related TDP-43 encephalopathy. The mechanism of TDP-43 phosphorylation is poorly understood. Previously we reported casein kinase 1 epsilon gene (CSNK1E gene encoding CK1ε protein) as being tightly correlated with phosphorylated TDP-43 (pTDP-43) pathology. Here we pursued studies to investigate in cellular models and in vitro how CK1ε and CK1δ (a closely related family sub-member) mediate TDP-43 phosphorylation in disease. We first validated the binding interaction between TDP-43 and either CK1δ and CK1ε using kinase activity assays and predictive bioinformatic database. We utilized novel inducible cellular models that generated translocated phosphorylated TDP-43 (pTDP-43) and cytoplasmic aggregation. Reducing CK1 kinase activity with siRNA or small molecule chemical inhibitors resulted in significant reduction of pTDP-43, in both soluble and insoluble protein fractions. We also established CK1δ and CK1ε are the primary kinases that phosphorylate TDP-43 compared to CK2α, CDC7, ERK1/2, p38α/MAPK14, and TTBK1, other identified kinases that have been implicated in TDP-43 phosphorylation. Throughout our studies, we were careful to examine both the soluble and insoluble TDP-43 protein fractions, the critical protein fractions related to protein aggregation diseases. These results identify CK1s as critical kinases involved in TDP-43 hyperphosphorylation and aggregation in cellular models and in vitro, and in turn are potential therapeutic targets by way of CK1δ/ε inhibitors.

Keywords:  Amyotrophic lateral sclerosis; Casein kinase 1 delta; Casein kinase 1 epsilon; Phosphorylation; TAR DNA-binding protein (TDP-43); TDP-43 proteinopathies

DOI:  https://doi.org/10.1016/j.nbd.2024.106516
Cell Death Dis. 2024 Apr 30. 15(4): 304

Actin-nucleation promoting factor N-WASP influences alpha-synuclein condensates and pathology.

Joshua Jackson, Christian Hoffmann, Enzo Scifo, Han Wang, Lena Wischhof, Antonia Piazzesi, Mrityunjoy Mondal, Hanna Shields, Xuesi Zhou, Magali Mondin, Eanna B Ryan, Hermann Döring, Jochen H M Prehn, Klemens Rottner, Gregory Giannone, Pierluigi Nicotera, Dan Ehninger, Dragomir Milovanovic, Daniele Bano.

Abnormal intraneuronal accumulation of soluble and insoluble α-synuclein (α-Syn) is one of the main pathological hallmarks of synucleinopathies, such as Parkinson's disease (PD). It has been well documented that the reversible liquid-liquid phase separation of α-Syn can modulate synaptic vesicle condensates at the presynaptic terminals. However, α-Syn can also form liquid-like droplets that may convert into amyloid-enriched hydrogels or fibrillar polymorphs under stressful conditions. To advance our understanding on the mechanisms underlying α-Syn phase transition, we employed a series of unbiased proteomic analyses and found that actin and actin regulators are part of the α-Syn interactome. We focused on Neural Wiskott-Aldrich syndrome protein (N-WASP) because of its association with a rare early-onset familial form of PD. In cultured cells, we demonstrate that N-WASP undergoes phase separation and can be recruited to synapsin 1 liquid-like droplets, whereas it is excluded from α-Syn/synapsin 1 condensates. Consistently, we provide evidence that wsp-1/WASL loss of function alters the number and dynamics of α-Syn inclusions in the nematode Caenorhabditis elegans. Together, our findings indicate that N-WASP expression may create permissive conditions that promote α-Syn condensates and their potentially deleterious conversion into toxic species.

DOI: https://doi.org/10.1038/s41419-024-06686-7
NPJ Parkinsons Dis. 2024 May 03. 10(1): 96

Misfolded protein deposits in Parkinson's disease and Parkinson's disease-related cognitive impairment, a [11C]PBB3 study.

Michele Matarazzo, Alexandra Pérez-Soriano, Nasim Vafai, Elham Shahinfard, Kevin Ju-Chieh Cheng, Jessamyn McKenzie, Nicole Neilson, Qing Miao, Paul Schaffer, Hitoshi Shinotoh, Jeffrey H Kordower, Vesna Sossi, A Jon Stoessl.

Parkinson's disease (PD) is associated with aggregation of misfolded α-synuclein and other proteins, including tau. We designed a cross-sectional study to quantify the brain binding of [11C]PBB3 (a ligand known to bind to misfolded tau and possibly α-synuclein) as a proxy of misfolded protein aggregation in Parkinson's disease (PD) subjects with and without cognitive impairment and healthy controls (HC). In this cross-sectional study, nineteen cognitively normal PD subjects (CN-PD), thirteen cognitively impaired PD subjects (CI-PD) and ten HC underwent [11C]PBB3 PET. A subset of the PD subjects also underwent PET imaging with [11C](+)DTBZ to assess dopaminergic denervation and [11C]PBR28 to assess neuroinflammation. Compared to HC, PD subjects showed higher [11C]PBB3 binding in the posterior putamen but not the substantia nigra. There was no relationship across subjects between [11C]PBB3 and [11C]PBR28 binding in nigrostriatal regions. [11C]PBB3 binding was increased in the anterior cingulate in CI-PD compared to CN-PD and HC, and there was an inverse correlation between cognitive scores and [11C]PBB3 binding in this region across all PD subjects. Our results support a primary role of abnormal protein deposition localized to the posterior putamen in PD. This suggests that striatal axonal terminals are preferentially involved in the pathophysiology of PD. Furthermore, our findings suggest that anterior cingulate pathology might represent a significant in vivo marker of cognitive impairment in PD, in agreement with previous neuropathological studies.

DOI: https://doi.org/10.1038/s41531-024-00708-z
Neurobiol Dis. 2024 Apr 26. pii: S0969-9961(24)00116-5. [Epub ahead of print] 106517

Age-dependent dynamics of neuronal VAPBALS inclusions in the adult brain.

Aparna Thulasidharan, Lovleen Garg, Shweta Tendulkar, Girish S Ratnaparkhi.

  Amyotrophic Lateral Sclerosis (ALS) is a relentlessly progressive and fatal disease, caused by the degeneration of upper and lower motor neurons within the brain and spinal cord in the ageing human. The dying neurons contain cytoplasmic inclusions linked to the onset and progression of the disease. Here, we use a Drosophila model of ALS8 (VAPP58S) to understand the modulation of these inclusions in the ageing adult brain. The adult VAPP58S fly shows progressive deterioration in motor function till its demise 25 days post-eclosion. The density of VAPP58S-positive brain inclusions is stable for 5-15 days of age. In contrast, adding a single copy of VAPWT to the VAPP58S animal leads to a large decrease in inclusion density with concomitant rescue of motor function and lifespan. ER stress, a contributing factor in disease, shows reduction with ageing for the disease model. Autophagy, rather than the Ubiquitin Proteasome system, is the dominant mechanism for aggregate clearance. We explored the ability of Drosophila Valosin-containing protein (VCP/TER94), the ALS14 locus, which is involved in cellular protein clearance, to regulate age-dependent aggregation. Contrary to expectation, TER94 overexpression increased VAPP58S punctae density, while its knockdown led to enhanced clearance. Expression of a dominant positive allele, TER94R152H, further stabilised VAPP58S puncta, cementing roles for an ALS8-ALS14 axis. Our results are explained by a mechanism where autophagy is modulated by TER94 knockdown. Our study sheds light on the complex regulatory events involved in the neuronal maintenance of ALS8 aggregates, suggesting a context-dependent switch between proteasomal and autophagy-based mechanisms as the larvae develop into an adult. A deeper understanding of the nucleation and clearance of the inclusions, which affect cellular stress and function, is essential for understanding the initiation and progression of ALS.

Keywords:  ALS14; ALS8; Ageing; Autophagy; FAF1; Neuroaggregate; TER94; VCP; Valosin; p97

DOI:  https://doi.org/10.1016/j.nbd.2024.106517