bims-proned 2025-01-12 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2025–01–12
twelve papers selected by
Verena Kohler, Umeå University

The Search for a Universal Treatment for Defined and Mixed Pathology Neurodegenerative Diseases.
Deciphering the Seed Size-Dependent Cellular Internalization Mechanism for α-Synuclein Fibrils.
Heterotypic Seeding Generates Mixed Amyloid Polymorphs.
Hydrophobic interaction of glycitein and α-synuclein inhibits the protein aggregation: A future perspective for modulation of Parkinson's disease.
DOPAC as a modulator of α-Synuclein and E46K interactions with membrane: Insights into binding dynamics.
Tubulin-Binding Region Modulates Cholesterol-Triggered Aggregation of Tau Proteins.
TFE3-mediated neuroprotection: Clearance of aggregated α-synuclein and accumulated mitochondria in the AAV-α-synuclein model of Parkinson's disease.
Inducers and modulators of protein aggregation in Alzheimer's disease - Critical tools for understanding the foundations of aggregate structures.
VCP regulates early tau seed amplification via specific cofactors.
Interaction of α-synuclein with DJ-1 in homodimer and L166P mutant monomer forms in Parkinson's disease: a molecular dynamics study.
Effects on neuroprotection and α-synuclein expression of a Canna coccinea rhizome extract.
Mechanisms of Alpha-Synuclein Seeded Aggregation in Neurons Revealed by Fluorescence Lifetime Imaging.

Int J Mol Sci. 2024 Dec 14. pii: 13424. [Epub ahead of print]25(24):

The Search for a Universal Treatment for Defined and Mixed Pathology Neurodegenerative Diseases.

Danton H O'Day.

  The predominant neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, dementia with Lewy Bodies, Huntington's disease, amyotrophic lateral sclerosis, and frontotemporal dementia, are rarely pure diseases but, instead, show a diversity of mixed pathologies. At some level, all of them share a combination of one or more different toxic biomarker proteins: amyloid beta (Aβ), phosphorylated Tau (pTau), alpha-synuclein (αSyn), mutant huntingtin (mHtt), fused in sarcoma, superoxide dismutase 1, and TAR DNA-binding protein 43. These toxic proteins share some common attributes, making them potentially universal and simultaneous targets for therapeutic intervention. First, they all form toxic aggregates prior to taking on their final forms as contributors to plaques, neurofibrillary tangles, Lewy bodies, and other protein deposits. Second, the primary enzyme that directs their aggregation is transglutaminase 2 (TGM2), a brain-localized enzyme involved in neurodegeneration. Third, TGM2 binds to calmodulin, a regulatory event that can increase the activity of this enzyme threefold. Fourth, the most common mixed pathology toxic biomarkers (Aβ, pTau, αSyn, nHtt) also bind calmodulin, which can affect their ability to aggregate. This review examines the potential therapeutic routes opened up by this knowledge. The end goal reveals multiple opportunities that are immediately available for universal therapeutic treatment of the most devastating neurodegenerative diseases facing humankind.

Keywords:  calcium dysregulation; calmodulin; mixed pathology; neurodegeneration; proteinopathies; toxic protein aggregation; transglutaminase 2

DOI:  https://doi.org/10.3390/ijms252413424
Biochemistry. 2025 Jan 06.

Deciphering the Seed Size-Dependent Cellular Internalization Mechanism for α-Synuclein Fibrils.

Arunima Sakunthala, Samir K Maji.

Aggregation of α-synuclein (α-Syn) and Lewy body (LB) formation are the key pathological events implicated in Parkinson's disease (PD) that spread in a prion-like manner. However, biophysical and structural characteristics of toxic α-Syn species and molecular events that drive early events in the propagation of α-Syn amyloids in a prion-like manner remain elusive. We used a neuronal cell model to demonstrate the size-dependent native biological activities of α-Syn fibril seeds. Biophysical characterization of the fibril seeds generated by controlled fragmentation indicated that increased fragmentation leads to a reduction in fibril size, correlating directly with the extent of fragmentation events. Although the size-based complexity of amyloid fibrils modulates their biological activities and fibril amplification pathways, it remains unclear how the variability of fibril seed size dictates its specific uptake mechanism into the cells. The present study elucidates the mechanism of α-Syn fibril internalization and how it is regulated by the size of fibril seeds. Further, we demonstrate that size-dependent endocytic pathways (dynamin-dependent clathrin/caveolin-mediated) are more prominent for the differential uptake of short fibril seeds compared to their longer counterparts. This size-dependent preference might contribute to the enhanced uptake and transcellular propagation of short α-Syn fibril seeds in a prion-like manner. Overall, the present study suggests that the physical dimension of α-Syn amyloid fibril seeds significantly influences their cellular uptake and pathological responses in the initiation and progression of PD.

DOI: https://doi.org/10.1021/acs.biochem.4c00667
Small Sci. 2024 Sep;pii: 2400109. [Epub ahead of print]4(9):

Heterotypic Seeding Generates Mixed Amyloid Polymorphs.

Siddhartha Banerjee, Divya Baghel, Harrison O Edmonds, Ayanjeet Ghosh.

  Aggregation of the amyloid β (Aβ) peptide into fibrils represents one of the major biochemical pathways underlying the development of Alzheimer's disease (AD). Extensive studies have been carried out to understand the role of fibrillar seeds on the overall kinetics of amyloid aggregation. However, the precise effect of seeds that are structurally or sequentially different from Aβ on the structure of the resulting amyloid aggregates is yet to be fully understood. Herein, nanoscale infrared spectroscopy is used to probe the spectral facets of individual aggregates formed by aggregating Aβ42 with antiparallel fibrillar seeds of Aβ(16-22) and E22Q Aβ(1-40) Dutch mutant and it is demonstrated that Aβ can form heterotypic or mixed polymorphs that deviate significantly from its expected parallel cross β structure. It is further shown that the formation of heterotypic aggregates is not limited to the coaggregation of Aβ and its isomers, and that the former can form heterotypic fibrils with alpha-synuclein and brain protein lysates. These findings highlight the complexity of Aβ aggregation in AD and underscore the need to explore how Aβ interacts with other brain components, which is crucial for developing better therapeutic strategies for AD.

Keywords:  Alzheimer’s disease; amyloid beta; atomic force microscopy-integrating infrared; infrared spectroscopy; nanoscale spectroscopy; protein aggregation

DOI:  https://doi.org/10.1002/smsc.202400109
Int J Biol Macromol. 2025 Jan 03. pii: S0141-8130(24)10247-4. [Epub ahead of print] 139436

Hydrophobic interaction of glycitein and α-synuclein inhibits the protein aggregation: A future perspective for modulation of Parkinson's disease.

Jikuang Zhao, Meiling Xiang, Qing Han, Xiaobai Yang, Guoguo Zhang, Youchao Xiao, Wu Zheng, Sheng Nie.

  Despite the worldwide prevalence of Parkinson's disease (PD), there are currently no effective methods for treating or preventing α-synucleinopathy. Research has demonstrated that small molecules are capable of preventing α-synuclein aggregation and the associated neurotoxicity. Nonetheless, the specific anti-amyloid mechanism of these compounds is not thoroughly comprehended in detail. In this study, the interaction between glycitein and α-synuclein was evaluated. Furthermore, the aggregation of α-synuclein in the presence of glycitein was examined utilizing several arrays. Thermodynamic results indicated that glycitein, an O-methylated isoflavone, binds to α-synuclein by creating a static complex, wherein non-covalent interactions, especially hydrophobic forces, served as the primary intermolecular forces stabilizing the complex. We further found that glycitein serves as a promising bioactive agent against α-synuclein amyloid fibrillation in a concentration-dependent fashion, modulating the formation of hydrophobic regions, the solution's surface tension, and the shift from natural random coil to β-sheet configurations, in addition to potential interactions with α-synuclein monomers and amyloid fibril formations. Moreover, we noted that glycitein prevents the neurotoxicity caused by α-synuclein aggregates by shielding PC12 cells from ROS production and caspase-3 activation. These results emphasize the significance of using bioactive small compounds for the prevention and treatment of PD.

Keywords:  Aggregation; Glycitein; Inhibition; Neurotoxicity; α-Synuclein

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.139436
Int J Biol Macromol. 2025 Jan 03. pii: S0141-8130(24)10238-3. [Epub ahead of print]294 139427

DOPAC as a modulator of α-Synuclein and E46K interactions with membrane: Insights into binding dynamics.

Elena Rizzotto, Andrea Pierangelini, Benedetta Fongaro, Manuela Leri, Ilenia Inciardi, Philipp Trolese, Vincenzo De Filippis, Monica Bucciantini, Laura Acquasaliente, Patrizia Polverino de Laureto.

  α-Synuclein (Syn) is an intrinsically disordered protein, abundant in presynaptic neurons. It is a constituent of the Lewis Body inclusions as amyloid fibrils, in Parkinson's disease patients. It populates an ensemble of conformations and floats between the free random coil and the membrane-bound α-helical species. E46K is a pathogenic mutant of Syn able to accelerate the formation of fibrils. The lysine in position 46 affects several protein structural properties including its interaction with membranes. We have shown that 3,4-dihydroxyphenylacetic acid (DOPAC), a dopamine metabolite, hampers Syn to form fibrils, interfering with the aggregation process and alters the interaction of the protein and its aggregates with membranes. To understand the mechanism of such alteration, we studied the interplay between Syn and E46K, lipid membranes and DOPAC. The ability of DOPAC to displace the proteins bound to membrane was also tested. Our findings provided a dynamic model of interaction able to explain the different effects of DOPAC on lipid binding properties of Syn and E46K, shedding light on the conformational changes induced by the catechol, which may destabilize the protein interactions with membranes. Understanding these mechanisms could have implications for therapeutic strategies targeting Syn aggregation and membrane interactions in neurodegenerative diseases.

Keywords:  Conformational studies; DOPAC; E46K familiar mutation; Membrane binding properties; α-Synuclein

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.139427
J Neurochem. 2025 Jan;169(1): e16294

Tubulin-Binding Region Modulates Cholesterol-Triggered Aggregation of Tau Proteins.

Abid Ali, Mikhail Matveyenka, Davis N Pickett, Axell Rodriguez, Dmitry Kurouski.

  A hallmark of Alzheimer disease (AD) and tauopathies, severe neurodegenerative diseases, is the progressive aggregation of Tau, also known as microtubule-associated Tau protein. Full-length Tau1-441, also known as 2N4R, contains two N-terminal inserts that bind to tubulin. This facilitates the self-assembly of tubulin simultaneously enhancing stability of cell microtubules. Other Tau isoforms have one (1N4R) or zero (0N4R) N-terminal inserts, which makes 2N4R Tau more and 0N4R less effective in promoting microtubule self-assembly. A growing body of evidence indicates that lipids can alter the aggregation rate of Tau isoforms. However, the role of N-terminal inserts in Tau-lipid interactions remains unclear. In this study, we utilized a set of biophysical methods to determine the extent to which N-terminal inserts alter interactions of Tau isoforms with cholesterol, one of the most important lipids in plasma membranes. Our results showed that 2 N insert prevents amyloid-driven aggregation of Tau at the physiological concentration of cholesterol, while the absence of this N-terminal repeat (1N4R and 0N4R Tau) resulted in the self-assembly of Tau into toxic amyloid fibrils. We also found that the presence of cholesterol in the lipid bilayers caused a significant increase in the cytotoxicity of 1N4R and 0N4R Tau to neurons. This effect was not observed for 2N4R Tau fibrils formed in the presence of lipid membranes with low, physiological, and elevated concentrations of cholesterol. Using molecular assays, we found that Tau aggregates primarily exert cytotoxicity by damaging cell endosomes, endoplasmic reticulum, and mitochondria.

Keywords:  Tau; amyloids; cholesterol; fibrils

DOI:  https://doi.org/10.1111/jnc.16294
Genes Dis. 2025 Mar;12(2): 101429

TFE3-mediated neuroprotection: Clearance of aggregated α-synuclein and accumulated mitochondria in the AAV-α-synuclein model of Parkinson's disease.

Xin He, Mulan Chen, Yepeng Fan, Bin Wu, Zhifang Dong.

  Parkinson's disease (PD) is a neurodegenerative disorder characterized by fibrillar neuronal inclusions containing aggregated α-synuclein (α-Syn). While the pathology of PD is multifaceted, the aggregation of α-Syn and mitochondrial dysfunction are well-established hallmarks in its pathogenesis. Recently, TFE3, a transcription factor, has emerged as a regulator of autophagy and metabolic processes. However, it remains unclear whether TFE3 can facilitate the degradation of α-Syn and regulate mitochondrial metabolism specifically in dopaminergic neurons. In this study, we demonstrate that TFE3 overexpression significantly mitigates the loss of dopaminergic neurons and reduces the decline in tyrosine hydroxylase-positive fiber density, thereby restoring motor function in an α-Syn overexpression model of PD. Mechanistically, TFE3 overexpression reversed α-Syn-mediated impairment of autophagy, leading to enhanced α-Syn degradation and reduced aggregation. Additionally, TFE3 overexpression inhibited α-Syn propagation. TFE3 overexpression also reversed the down-regulation of Parkin, promoting the clearance of accumulated mitochondria, and restored the expression of PGC1-α and TFAM, thereby enhancing mitochondrial biogenesis in the adeno-associated virus-α-Syn model. These findings further underscore the neuroprotective role of TFE3 in PD and provide insights into its underlying mechanisms, suggesting TFE3 as a potential therapeutic target for PD.

Keywords:  Autophagy; Mitochondrial biogenesis; Mitophagy; Parkinson's disease; TFE3; α-synuclein

DOI:  https://doi.org/10.1016/j.gendis.2024.101429
Neurotherapeutics. 2025 Jan 03. pii: S1878-7479(24)00199-5. [Epub ahead of print] e00512

Inducers and modulators of protein aggregation in Alzheimer's disease - Critical tools for understanding the foundations of aggregate structures.

Kerry T Sun, Sue-Ann Mok.

  Amyloidogenic protein aggregation is a pathological hallmark of Alzheimer's Disease (AD). As such, this critical feature of the disease has been instrumental in guiding research on the mechanistic basis of disease, diagnostic biomarkers and preventative and therapeutic treatments. Here we review identified molecular triggers and modulators of aggregation for two of the proteins associated with AD: amyloid beta and tau. We aim to provide an overview of how specific molecular factors can impact aggregation kinetics and aggregate structure to promote disease. Looking toward the future, we highlight some research areas of focus that would accelerate efforts to effectively target protein aggregation in AD.

Keywords:  Aggregate structure; Aggregation; Amyloid; Amyloid beta; Tau

DOI:  https://doi.org/10.1016/j.neurot.2024.e00512
Mol Neurodegener. 2025 Jan 07. 20(1): 2

VCP regulates early tau seed amplification via specific cofactors.

Sushobhna Batra, Jaime Vaquer-Alicea, Clarissa Valdez, Skyler P Taylor, Victor A Manon, Anthony R Vega, Omar M Kashmer, Sourav Kolay, Andrew Lemoff, Nigel J Cairns, Charles L White, Marc I Diamond.

   BACKGROUND: Neurodegenerative tauopathies may progress based on seeding by pathological tau assemblies, whereby an aggregate is released from one cell, gains entry to an adjacent or connected cell, and serves as a specific template for its own replication in the cytoplasm. Seeding into the complex cytoplasmic milieu happens within hours, implying the existence of unknown factors that regulate this process.
METHODS: We used proximity labeling to identify proteins that control seed amplification within 5 h of seed exposure. We fused split-APEX2 to the C-terminus of tau repeat domain (RD) to reconstitute peroxidase activity 5 h after seeded intracellular tau aggregation. Valosin containing protein (VCP/p97) was the top hit. VCP harbors dominant mutations that underlie two neurodegenerative diseases, multisystem proteinopathy and vacuolar tauopathy, but its mechanistic role is unclear. We used immortalized cells and human neurons to study the effects of VCP on tau seeding. We exposed cells to fibrils or brain homogenates in cell culture media and measured effects on uptake and induction of intracellular tau aggregation following various genetic and pharmacological manipulations of VCP.
RESULTS: VCP knockdown reduced tau seeding. Chemical inhibitors had opposing effects on seeding in HEK293T tau biosensor cells and human neurons: ML-240 increased seeding efficiency, whereas NMS-873 decreased it. The inhibitors only functioned when administered within 8 h of seed exposure, indicating a role for VCP early in seed processing. We screened 30 VCP co-factors in HEK293T biosensor cells by genetic knockout or knockdown. Reduction of ATXN3, NSFL1C, UBE4B, NGLY1, and OTUB1 decreased tau seeding, as did NPLOC4, which also uniquely increased soluble tau levels. By contrast, reduction of FAF2 increased tau seeding.
CONCLUSIONS: Divergent effects on tau seeding of chemical inhibitors and cofactor reduction indicate that VCP regulates this process. This is consistent with a cytoplasmic processing complex centered on VCP that directs seeds acutely towards degradation vs. amplification.

Keywords:  APEX2; Cofactors; Disaggregase; Seeding; Tau; VCP; p97

DOI:  https://doi.org/10.1186/s13024-024-00783-z
J Biomol Struct Dyn. 2025 Jan 08. 1-8

Interaction of α-synuclein with DJ-1 in homodimer and L166P mutant monomer forms in Parkinson's disease: a molecular dynamics study.

Mozhgan Alipour, Behnam Hajipour-Verdom, Alireza Zali, Farzad Ashrafi, Parviz Abdolmaleki, Saeed Oraee-Yazdani, Meisam Akhlaghdoust, Nastaran Karimi.

  Parkinson's disease (PD) is a progressive neurodegenerative disorder that is characterized by the formation of Lewy bodies, which are primarily composed of misfolded α-Synuclein (α-Syn). DJ-1 is a crucial protein involved in the correct folding of α-Syn, and mutations impairing its function are associated with the onset of PD. One such mutation, the L166P substitution in DJ-1, which has been linked to early-onset PD and results in the loss of DJ-1's homodimer structure. Recent studies have shown the presence of DJ-1 in Lewy bodies, but its interaction with α-Syn is unknown. Therefore, in this study, we investigated the interaction between α-Syn and DJ-1 in both its wild-type (wDJ-1: homodimer) and L166P mutant (mDJ-1: monomer) forms using molecular dynamics simulation. Our results indicated that α-Syn binds more tightly to mDJ-1 than to wDJ-1. Gibbs free energy landscape analysis showed that the bonded α-Syn to mDJ-1 complex represents a stable conformation, whereas only a partial connection of α-Syn to wDJ-1 was observed. Generally, it appears that the monomer form of DJ-1 resulting from the L166P mutation can form a stable complex with α-Syn, potentially intensifying the formation of Lewy bodies. Thus, the identification of aggregated α-Syn with DJ-1 may serve as a potential biomarker for PD.

Keywords:  DJ-1 protein; L166P mutant; Parkinson’s disease; molecular dynamics simulation; α-Synuclein

DOI:  https://doi.org/10.1080/07391102.2024.2446660
Fitoterapia. 2025 Jan 05. pii: S0367-326X(25)00005-X. [Epub ahead of print]181 106380

Effects on neuroprotection and α-synuclein expression of a Canna coccinea rhizome extract.

Viviana G Spotorno, Mariana Roxo, Bernhard Wetterauer, Osvaldo A Zabal, Michael Wink.

  Parkinson's disease (PD) is the second most common neurodegenerative disorder in the elderly, currently with no cure. Its mechanisms are not well understood, however α-synuclein protein aggregation plays a central role in the pathogenesis of PD, leading to neurodegeneration. We demonstrated that in a PD model dietary in Caenorhabditis elegans treatment with an extract from the rhizome of Canna coccinea decreased the accumulation of α-synuclein. The extract showed low toxicity to neuro 2a cells and protected them from oxidative damage with H2O2 as a model for neurodegeneration. We studied the chemical profile of the extract using liquid chromatography couple to Mass Spectrometry. In order to characterize the herbal extract, we quantified rosmarinic acid as a marker compound and measured its antioxidant activity in vitro. Altogether, apart from its potential as a functional food, Canna coccinea may be an interesting source of secondary metabolites in the development of potential novel anti-neurodegenerative drugs.

Keywords:  Caenorhabditis elegans; Canna coccinea; Canna índica; Neuro 2 a; Neuroprotection; Parkinson's disease; α-Synuclein

DOI:  https://doi.org/10.1016/j.fitote.2025.106380
bioRxiv. 2024 Dec 17. pii: 2024.12.16.628520. [Epub ahead of print]

Mechanisms of Alpha-Synuclein Seeded Aggregation in Neurons Revealed by Fluorescence Lifetime Imaging.

Paula-Marie E Ivey, Magaly Guzman Sosa, Abdelrahman Salem, Sehong Min, Wenzhu Qi, Alicia N Scott, Karin F K Ejendal, Tamara L Kinzer-Ursem, Jean-Christophe Rochet, Kevin J Webb.

1The brains of Parkinson's disease (PD) patients are characterized by the presence of Lewy body inclusions enriched with fibrillar forms of the presynaptic protein alpha-synuclein (aSyn). Despite related evidence that Lewy pathology spreads across different brain regions as the disease progresses, the underlying mechanism hence the fundamental cause of PD progression is unknown. The propagation of aSyn pathology is thought to potentially occur through the release of aSyn aggregates from diseased neurons, their uptake by neighboring healthy neurons via endocytosis, and subsequent seeding of native aSyn aggregation in the cytosol. A critical aspect of this process is believed to involve the escape of internalized ag-gregates from the endolysosomal compartment, though direct evidence of this mechanism in cultured neuron models remains lacking. In this study, we utilize a custom-built, time-gated fluorescence lifetime imaging microscope (FLIM) to investigate the progression of seeded ag-gregation over time in live cortical neurons. By establishing fluorescence lifetime sensitivity to aSyn aggregation level, we are able to monitor the protein's aggregation state. Through a FLIM analysis of neurons expressing aSyn-mVenus and exposed to aSyn preformed fibrils labeled with the acid-responsive dye pHrodo, we reveal the protein's aggregation state in both the cytosol and the endolysosomal compartment. The results indicate that aSyn seeds undergo partial disassembly prior to escaping the endocytic pathway, and that this escape is closely linked to the aggregation of cytosolic aSyn. In certain neurons, monomeric aSyn is found to translocate from the cytosol into the endolysosomal compartment, where it appar-ently forms aggregates in proximity to retained seeds. Additional analyses reveals zones of neuritic aSyn aggregates that overlaps with regions of microtubule disruption. Collectively, these findings enhance our understanding of aSyn pathology propagation in PD and other synucleinopathies, motivate additional experiments along these lines, and offer a path to guide the development of disease-modifying therapies.

DOI: https://doi.org/10.1101/2024.12.16.628520