bims-proned 2025-04-13 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2025–04–13
ten papers selected by
Verena Kohler, Umeå University

Activating autophagy to eliminate toxic protein aggregates with small molecules in neurodegenerative diseases.
α-synuclein and tau: interactions, cross-seeding, and the redefinition of synucleinopathies as complex proteinopathies.
Green tea polyphenol EGCG acts differentially on end-stage amyloid polymorphs of α-synuclein formed in different polyol osmolytes.
Peptidomimetics Activating the Proteasome: A New Perspective for Parkinson's Treatment.
Malondialdehyde Mediated Alpha-Synuclein Aggregation: A Plausible Etiology of Parkinson's Disease in Oxidative Stress.
Gene delivery of a SUMO1-derived peptide rescues neuronal degeneration and motor deficits in an rAAV-α-synuclein-A53T mouse model of Parkinson's disease.
α-Synuclein interacts directly with AP2 and regulates its binding to synaptic membranes.
Targeting neurodegenerative disease-associated protein aggregation with proximity-inducing modalities.
Membrane Charge Drives the Aggregation of TDP-43 Pathological Fragments.
Internalization of extracellular Tau oligomers in Alzheimer's disease.

Pharmacol Rev. 2025 Mar 14. pii: S0031-6997(25)07461-7. [Epub ahead of print]77(3): 100053

Activating autophagy to eliminate toxic protein aggregates with small molecules in neurodegenerative diseases.

Yuqi Fu, Jin Zhang, Rui Qin, Yueting Ren, Tingting Zhou, Bo Han, Bo Liu.

Neurodegenerative diseases (NDs), such as Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, and frontotemporal dementia, are well known to pose formidable challenges for their treatment due to their intricate pathogenesis and substantial variability among patients, including differences in environmental exposures and genetic predispositions. One of the defining characteristics of NDs is widely reported to be the buildup of misfolded proteins. For example, Alzheimer disease is marked by amyloid beta and hyperphosphorylated Tau aggregates, whereas Parkinson disease exhibits α-synuclein aggregates. Amyotrophic lateral sclerosis and frontotemporal dementia exhibit TAR DNA-binding protein 43, superoxide dismutase 1, and fused-in sarcoma protein aggregates, and Huntington disease involves mutant huntingtin and polyglutamine aggregates. These misfolded proteins are the key biomarkers of NDs and also serve as potential therapeutic targets, as they can be addressed through autophagy, a process that removes excess cellular inclusions to maintain homeostasis. Various forms of autophagy, including macroautophagy, chaperone-mediated autophagy, and microautophagy, hold a promise in eliminating toxic proteins implicated in NDs. In this review, we focus on elucidating the regulatory connections between autophagy and toxic proteins in NDs, summarizing the cause of the aggregates, exploring their impact on autophagy mechanisms, and discussing how autophagy can regulate toxic protein aggregation. Moreover, we underscore the activation of autophagy as a potential therapeutic strategy across different NDs and small molecules capable of activating autophagy pathways, such as rapamycin targeting the mTOR pathway to clear α-synuclein and Sertraline targeting the AMPK/mTOR/RPS6KB1 pathway to clear Tau, to further illustrate their potential in NDs' therapeutic intervention. Together, these findings would provide new insights into current research trends and propose small-molecule drugs targeting autophagy as promising potential strategies for the future ND therapies. SIGNIFICANCE STATEMENT: This review provides an in-depth overview of the potential of activating autophagy to eliminate toxic protein aggregates in the treatment of neurodegenerative diseases. It also elucidates the fascinating interrelationships between toxic proteins and the process of autophagy of "chasing and escaping" phenomenon. Moreover, the review further discusses the progress utilizing small molecules to activate autophagy to improve the efficacy of therapies for neurodegenerative diseases by removing toxic protein aggregates.

DOI: https://doi.org/10.1016/j.pharmr.2025.100053
Front Neurosci. 2025 ;19 1570553

α-synuclein and tau: interactions, cross-seeding, and the redefinition of synucleinopathies as complex proteinopathies.

Francisco J Padilla-Godínez, Eunice Ruth Vázquez-García, María Isabel Trujillo-Villagrán, Luis O Soto-Rojas, Marcela Palomero-Rivero, Omar Hernández-González, Francisco Pérez-Eugenio, Omar Collazo-Navarrete, Oscar Arias-Carrión, Magdalena Guerra-Crespo.



Keywords:  Lewy bodies; proteinopathy; synucleinopathy; tau; tauopathy; α-synuclein

DOI:  https://doi.org/10.3389/fnins.2025.1570553
Biochim Biophys Acta Proteins Proteom. 2025 Apr 04. pii: S1570-9639(25)00011-1. [Epub ahead of print]1873(4): 141073

Green tea polyphenol EGCG acts differentially on end-stage amyloid polymorphs of α-synuclein formed in different polyol osmolytes.

Santosh Devi, Dushyant K Garg, Rajiv Bhat.

  Synucleinopathies are heterogenous group of disorders characterized by α-synuclein amyloid aggregates in the nervous system. Different synucleinopathy clinical subtypes are encoded by structurally diverse α-synuclein amyloid polymorphs referred to as 'strains'. The underlying structural differences between polymorphs can potentially hamper the drug design against synucleinopathies. Polyphenolic compounds like EGCG have shown promise in inhibiting and remodeling of α-synuclein amyloid aggregates, but their effects on different polymorphs are not well-studied. The cellular environment is one factor contributing to the heterogeneity in the amyloid landscape. Herein, we generated diverse polymorphs of α-synuclein by fine-tuning its aggregation using different polyol osmolytes, varying in their physicochemical properties. These osmolytes act as globular protein stabilizers and conformational modulators of intrinsically disordered proteins. While the buffer control α-synuclein aggregates were evenly dispersed, the polyol-induced aggregate solutions contained a heterogeneous mixture of co-existing polymorphs, as evidenced by AFM and TEM measurements. The polyol-induced aggregated solutions consisted of a mixture of both fibrillar and nonfibrillar cross-β-rich species. Using various spectroscopic tools, we observed differences in the structures of osmolyte-induced polymorphic aggregates. We incubated these aggregates with EGCG and observed its disparate action over polymorphs wherein the treated species were either disintegrated or structurally altered. Contrary to previous reports, all EGCG-treated polymorphs were β-sheet-rich and seeding-competent. Our findings are relevant in assessing the efficacy of polyphenolic compounds on diverse aggregate strains encoding different proteinopathy variants. The formation of β-sheet-rich species in our study also engenders a more critical examination of EGCG's mode of action on diverse classes of amyloids.

Keywords:  Amyloid polymorphism; EGCG; Osmolytes: Non-fibrillar aggregates; Α-Synuclein

DOI:  https://doi.org/10.1016/j.bbapap.2025.141073
J Med Chem. 2025 Apr 07.

Peptidomimetics Activating the Proteasome: A New Perspective for Parkinson's Treatment.

Karolina Trepczyk, Safak Er, Irena Hlushchuk, Mikko Airavaara, Anna Alwani, Katarzyna Maziarz, Piotr Chmielarz, Kinga Słomska, Ewa Wieczerzak, Elżbieta Jankowska.

The development of age-related neurodegenerative diseases is associated with the accumulation of damaged and misfolded proteins. Such proteins are eliminated from cells by proteolytic systems, mainly by 20S proteasomes, whose activity declines with age. Its stimulation has been recognized as a promising approach to delay the onset or ameliorate the symptoms of neurodegenerative disorders. Here we present peptidomimetics that are very effective in stimulating the proteasome in biochemical assays and in cell culture. They are stable in human plasma and capable of penetrating the cell membranes. The activators demonstrated the ability to enhance h20S degradation of α-synuclein and tau, whose aggregates are involved in the development of Parkinson's and Alzheimer's diseases, respectively. The peptidomimetics did not show cytotoxicity to HEK293T and primary hippocampal cells. Additionally, these compounds were highly effective in reducing the amount of phosphorylated α-synuclein aggregates in hippocampal neurons in a mouse embryonic cell model.

DOI: https://doi.org/10.1021/acs.jmedchem.5c00645
Chem Res Toxicol. 2025 Apr 07.

Malondialdehyde Mediated Alpha-Synuclein Aggregation: A Plausible Etiology of Parkinson's Disease in Oxidative Stress.

Harsh Thakkar, Sayan Chatterjee, Arvind Verma, Naveen Chandrasekar, Amit Khairnar, Ravi P Shah.

Malondialdehyde (MDA), a major reactive byproduct of lipid peroxidation, has been implicated in numerous pathological conditions as a result of altering the structure and function of crucial proteins. One such protein is α-synuclein (α-Syn), which plays a vital role in the pathogenesis of Parkinson's disease (PD). This study investigates the hypothesis that MDA causes structural alterations in α-Syn, promoting its aggregation and exacerbating its toxicological effects. In vivo experiments were conducted where MDA and MDA-modified α-Syn were injected to the brain of mice. Behavioral assessments were performed to evaluate motor function changes, while immunohistochemistry was employed to examine the extent of α-Syn aggregation in brain tissues. An extraction protocol was also developed exquisitely, enabling quantification of modified α-Syn from brain tissue. Moreover, 15Nitrogen-labeled α-Syn was employed to establish an absolute quantification method on nLC-HRMS/MS. Our findings demonstrate that MDA-induced modifications in α-Syn alter its structural properties and also significantly enhance its aggregation propensity, potentially contributing to the neurodegenerative processes observed in PD. The developed model displayed a nonreversible decline in motor function, neurodegeneration, and aggregation of proteins in the brain mimicking the PD conditions. This research provides valuable insights into the molecular mechanisms of PD, emphasizing the role of MDA-modified proteins in the etiology of PD.

DOI: https://doi.org/10.1021/acs.chemrestox.4c00348
Mol Ther. 2025 Apr 05. pii: S1525-0016(25)00279-5. [Epub ahead of print]

Gene delivery of a SUMO1-derived peptide rescues neuronal degeneration and motor deficits in an rAAV-α-synuclein-A53T mouse model of Parkinson's disease.

Zhaohui Liang, Suresh Kanna Murugappan, Yuxuan Li, Man Nga Lai, Yajing Qi, Yi Wang, Ho Yin Edwin Chan, Marianne M Lee, Michael K Chan.

Developing α-synuclein aggregation inhibitors is challenging because its aggregation process involves several microscopic steps and heterogenous intermediates. Previously, we identified a SUMO1-derived peptide, SUMO1(15-55), that exhibits tight binding to monomeric α-synuclein via SUMO-SIM interactions, and effectively blocks the initiation of aggregation and formation of toxic aggregates in vitro. In cellular and Drosophila models, SUMO1(15-55) was efficacious in protecting neuronal cells from α-synuclein-induced neurotoxicity and neuronal degeneration. Given the demonstrated ability of SUMO1(15-55) to sequester α-synuclein monomers thereby blocking oligomers formation, we sought to evaluate whether it could be equally effective against the aggregation-prone familial mutant α-synuclein-A53T. Herein, we show that SUMO1(15-55) selectively binds to monomeric α-synuclein-A53T, inhibits primary nucleation, and prevents the formation of structured protofibrils in vitro, thereby protecting neuronal cells from protofibril-induced cell death. We further demonstrate that larval feeding of a designed His10-SUMO1(15-55) that exhibits enhanced sub-stoichiometric suppression of α-synuclein-A53T aggregation in vitro can ameliorate PD-related symptoms in α-synuclein-A53T transgenic Drosophila models, while its rAAV-mediated gene delivery can relieve the PD-related histological and behavioral deficiencies in an rAAV-α-synuclein-A53T mouse PD model. Our findings suggest that gene delivery of His10-SUMO1(15-55) may serve as a clinical therapy for a spectrum of α-synuclein-aggregation associated synucleinopathies.

DOI: https://doi.org/10.1016/j.ymthe.2025.04.005
J Biol Chem. 2025 Apr 09. pii: S0021-9258(25)00351-5. [Epub ahead of print] 108502

α-Synuclein interacts directly with AP2 and regulates its binding to synaptic membranes.

Karina J Vargas, Jaqulin N Wallace, Ian Mooney, David J Owen, Jennifer R Morgan.

  α-Synuclein mutation and aggregation are associated with several neurodegenerative disorders, including Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. It is expressed in the presynaptic compartment where it regulates clathrin mediated synaptic vesicle endocytosis. We have shown that α-synuclein regulates clathrin lattice size and curvature in vitro. However, the molecular mechanism by which this occurs remains unknown. Here, we show a strong colocalization between the heterotetrametric clathrin adaptor protein-2 (AP2) and α-synuclein at presynapses. Moreover, we report a direct biochemical interaction between the AP2 core domain and the C-terminal domain of α-synuclein. We further show that α-synuclein binds to isolated synaptic membranes in an ATP-dependent manner, similar to AP2 and the monomeric adaptor protein, 180 KDa (AP180), suggesting that α-synuclein, AP2 and AP180 share a common synaptic membrane binding pathway. In contrast, other endocytic proteins, such as clathrin heavy chain and the large GTPase dynamin-1 bind to synaptic membranes independently of ATP. After immunodepleting α-synuclein, we observed a specific reduction in AP2 binding to synaptic membranes, indicating that α-synuclein interaction with AP2 is necessary to maintain normal levels of AP2 on synaptic membranes. These findings demonstrate that α-synuclein plays a critical role in stabilizing AP2 on synaptic membranes, an event which is required for initiation of clathrin-mediated synaptic vesicle endocytosis.

Keywords:  AP2; endocytosis; synapse; synaptic vesicle recycling; α-synuclein

DOI:  https://doi.org/10.1016/j.jbc.2025.108502
Acta Pharmacol Sin. 2025 Apr 07.

Targeting neurodegenerative disease-associated protein aggregation with proximity-inducing modalities.

Rui-Xin Ge, Miao Chen, Qing-Chao Li, Min Liu, Jun Zhou, Song-Bo Xie.

  Neurodegenerative diseases (NDDs) are characterized by progressive neuronal dysfunction and anatomical changes caused by neuron loss and gliosis, ultimately leading to severe declines in brain function. While these disorders arise from a variety of pathological mechanisms, a common molecular feature is the accumulation of misfolded proteins, which occurs both inside and outside neurons. For example, Alzheimer's disease (AD) is defined by extracellular β-amyloid plaques and intracellular tau neurofibrillary tangles. These pathological protein aggregates are often resistant to traditional small molecule drugs. Recent advances in proximity-inducing chimeras such as proteolysis-targeting chimeras (PROTACs), lysosome-targeting chimeras (LYTACs), autophagy-targeted chimeras (AUTOTACs), dephosphorylation-targeting chimeras (DEPTACs) and ribonuclease-targeting chimeras (RIBOTACs) offer promising strategies to eliminate pathological proteins or mRNAs through intracellular degradation pathways. These innovative approaches open avenues for developing new therapies for NDDs. In this review we summarize the regulatory mechanisms of protein aggregation, highlight the advancements in proximity-inducing modalities for NDDs, and discuss the current challenges and future directions in therapeutic development.

Keywords:  AUTOTAC; DEPTAC; LYTAC; PROTAC; RIBOTAC; neurodegenerative diseases

DOI:  https://doi.org/10.1038/s41401-025-01538-2
J Am Chem Soc. 2025 Apr 08.

Membrane Charge Drives the Aggregation of TDP-43 Pathological Fragments.

Giacomo Corucci, Devkee M Vadukul, Nicolò Paracini, Valérie Laux, Krishna C Batchu, Francesco A Aprile, Annalisa Pastore.

TDP-43 protein is an RNA-binding protein linked to amyotrophic lateral sclerosis, frontotemporal dementia, and Alzheimer disease. While normally a protein that shuttles between the nucleus and cytoplasm, TDP-43 has recently been found also in extracellular vesicles. These are an important medium for cell-cell communication that allows the transfer of lipids, proteins, and genetic material among cells. An increasing concern in neurodegenerative diseases, however, is the possibility that extracellular vesicles can also provide an effective way to spread misfolded proteins that could "infect" other cells according to a "prion-like" mechanism. To characterize the interaction of TDP-43 with lipid membranes, we carried out a systematic biophysical study using a TDP-43 fragment lacking the first 84 N-terminal residues, called M85, and synthetic model phospholipid membranes. We utilized standard techniques, such as fluorescence and microscopy, complemented by neutron reflectivity measurements. Our results show that lipid charge affects the modality by which M85 interacts with membranes: a higher negative charge induces the protein to bind to the bilayer surface, promoting protein aggregation and decreasing lipid bilayer damage that this interaction causes. Thus, we speculate that the M85-lipid membrane interaction could play an important and previously undefined role in TDP-43-related neurodegenerative diseases.

DOI: https://doi.org/10.1021/jacs.5c00594
Adv Clin Chem. 2025 ;pii: S0065-2423(25)00016-2. [Epub ahead of print]126 1-29

Internalization of extracellular Tau oligomers in Alzheimer's disease.

Subashchandrabose Chinnathambi, Nagaraj Rangappa, Madhura Chandrashekar.

  A key factor in the progression of Alzheimer's disease (AD) is internalization of extracellular Tau oligomers (ecTauOs) by neuroglial cells. Aberrant hyperphosphorylation of Tau results in their dissociation from microtubules and formation of toxic intracellular Tau oligomers (icTauOs). These are subsequently released to the extracellular space following neuronal dysfunction and death. Although receptor mediated internalization of these ecTauOs by other neurons, microglia and astrocytes can facilitate elimination, incomplete degradation thereof promotes inflammation, exacerbates pathologic spread and accelerates neurodegeneration. Targeting Tau oligomer degradation pathways, blocking internalization receptors, and mitigating neuroinflammation are proposed as therapeutic strategies to control Tau propagation and toxicity. This review highlights the urgent need for innovative approaches to prevent the spread of Tau pathology, emphasizing its implications for AD and related neurodegenerative diseases.

Keywords:  Astrocytes; Microglia; Neurons; Tau internalization; Tau oligomers; Tauopathies

DOI:  https://doi.org/10.1016/bs.acc.2025.01.005