bims-proned 2025-07-27 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2025–07–27
twenty papers selected by
Verena Kohler, Umeå University

Co-Expression of Mutant Tau and α-Synuclein in Neurons Promotes Tau Phosphorylation, Neuronal Loss, and Neuroinflammation in Mouse Brain.
Protein Misfolding and Aggregation as a Mechanistic Link Between Chronic Pain and Neurodegenerative Diseases.
Oleuropein Aglycone, an Olive Polyphenol, Influences Alpha-Synuclein Aggregation and Exerts Neuroprotective Effects in Different Parkinson's Disease Models.
How does protein aggregate structure affect mechanisms of disaggregation?
Unraveling the mystery: How autophagy deficiency in dopaminergic neurons drives human Parkinson's disease.
Protein regulatory network mediated by palmitoylation modifications in the pathological progression of Parkinson's disease: a narrative review.
Self-driving microscopy detects the onset of protein aggregation and enables intelligent Brillouin imaging.
Tau Oligomers in Alzheimer's Disease: Modulation Effect of Osmolytes on Amplified Brain-Derived Tau Oligomers.
Role of the chaperonin TCP-1 ring complex in protein aggregation and neurodegeneration.
The emerging role of eIF5A hypusination as a unique and underexplored mechanism in proteinopathies and neurological diseases.
The Yeast Parkinson's Disease Model Exhibits An Increase in Peroxisome Number Independent of the Division Proteins Vps1 and Dnm1.
Secretory autophagy mediates lysosomal and autophagic degradation for α-synuclein proteostasis.
Investigation of Methylsulfonamide's Capability to Prevent Zn2+-Induced Aβ Peptide Aggregation Based on Zn2+ Coordination within the Zinc Binding Region of Aβ for Treatment of Alzheimer's Disease (AD).
Rapid and inducible mislocalization of endogenous TDP43 in a novel human model of amyotrophic lateral sclerosis.
Targeting ASK1 signaling in neurodegeneration: molecular insights and therapeutic promise.
Subtle concentration changes in zinc hold the key to fibrillation of α-synuclein: an updated insight on the micronutrient's role in prevention of neurodegenerative disorders.
Triggering ferroptosis in neurodegenerative diseases.
Trimeric superoxide dismutase 1 antibody as a universal biomarker for ALS.
Emergence of Compact Oligomers inside the Small-World Network of TDP-43 Condensates.
Copper metabolism and cuproptosis in Alzheimer's disease: mechanisms and therapeutic potential.

Mol Neurobiol. 2025 Jul 25.

Co-Expression of Mutant Tau and α-Synuclein in Neurons Promotes Tau Phosphorylation, Neuronal Loss, and Neuroinflammation in Mouse Brain.

Yuki Yamamoto, Toshiki Kubota, Daisuke Noguchi, Takaomi C Saido, Toshio Ohshima.

  Intracellular aggregation and accumulation of protein is a hallmark of neurodegenerative diseases. Tauopathy, which is caused by aggregated tau accumulation, is a group of neurodegenerative diseases, including frontotemporal dementia (FTD), Pick disease, and Alzheimer's disease. Similarly, synucleinopathy, which is caused by aggregated α-synuclein (α-syn) accumulation, includes Parkinson's disease and dementia with Lewy body (DLB). The interaction between tau and α-syn has been attracting attention because of similarities in symptoms and the co-existence of tau and α-syn in neural cells. Previous studies revealed that tau and α-syn promote their aggregation with each other. Additionally, other studies showed that α-syn promotes tau spreading in the mouse brain. In the present study, we investigated the relationship between tau and α-syn and the effects of their co-existence in neuronal cells on mouse pathology by double transgenic strategy. Consequently, we found increased phosphorylated tau, a declined number of neurons in the CA1 region, and increased astrocyte and microglia in the hippocampi in double transgenic mice at 8 months old. In mice that co-express tau and α-syn, locomotive activity increased and cognitive function decreased in behavioral test. These results suggest the co-existence of tau andα-syn in neurons that promote neuronal loss and impaired cognitive function in neurodegenerative conditions.

Keywords:  Accumulation; Aggregation; Tauopathy

DOI:  https://doi.org/10.1007/s12035-025-05248-y
Curr Issues Mol Biol. 2025 Apr 08. pii: 259. [Epub ahead of print]47(4):

Protein Misfolding and Aggregation as a Mechanistic Link Between Chronic Pain and Neurodegenerative Diseases.

Nebojsa Brezic, Strahinja Gligorevic, Aleksandar Sic, Nebojsa Nick Knezevic.

  Chronic pain, defined by persistent pain beyond normal healing time, is a pervasive and debilitating condition affecting up to 30-50% of adults globally. In parallel, neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are characterized by progressive neuronal loss and cognitive or motor decline, often underpinned by pathological protein misfolding and aggregation. Emerging evidence suggests a potential mechanistic link between chronic pain and NDs, with persistent pain contributing to neuroinflammatory states and protein homeostasis disturbances that mirror processes in neurodegeneration. This review explores the hypothesis that protein misfolding and aggregation serve as a mechanistic bridge between chronic pain and neurodegeneration. We systematically examine molecular pathways of protein misfolding, proteostasis dysfunction in chronic pain, and shared neuroimmune mechanisms, highlighting prion-like propagation of misfolded proteins, chronic neuroinflammation, and oxidative stress as common denominators. We further discuss evidence from experimental models and clinical studies linking chronic pain to accelerated neurodegenerative pathology-including tau accumulation, amyloid dysregulation, and microglial activation-and consider how these insights open avenues for novel therapeutics. Targeting protein aggregation, enhancing chaperone function, modulating the unfolded protein response (UPR), and attenuating glial activation are explored as potential strategies to mitigate chronic pain and possibly slow neurodegeneration. Understanding this intersection not only elucidates chronic pain's role in cognitive decline but also suggests that interventions addressing proteostasis and inflammation could yield dual benefits in pain management and neurodegenerative disease modification.

Keywords:  chronic pain; endoplasmic reticulum stress; neurodegenerative diseases; neuroinflammation; protein aggregation; protein misfolding; unfolded protein response

DOI:  https://doi.org/10.3390/cimb47040259
Mol Neurobiol. 2025 Jul 24.

Oleuropein Aglycone, an Olive Polyphenol, Influences Alpha-Synuclein Aggregation and Exerts Neuroprotective Effects in Different Parkinson's Disease Models.

Milo J Basellini, José M Granadino-Roldán, Pablo V Torres-Ortega, Giulia Simmini, Jaime Rubio-Martinez, Silvia Marin, Graziella Cappelletti, Marta Cascante, Ana Cañuelo.

  Α-synuclein aggregation is the pathological feature of several neurodegenerative disorders, including Parkinson's disease. The aggregates can diffuse within brain areas, and their toxicity has been proven in both cellular and animal models. Given that, recent therapeutic strategies have been focusing on the identification of compounds able to promote the degradation of aggregates or, at least, to prevent the aggregation process. In this field, the use of natural-derived polyphenols has been proposed as a potential tool against α-synuclein pathology. On these bases, we tested the neuroprotective potential of oleuropein aglycone, an olive polyphenol, in two cellular and C. elegans-based models of Parkinson's disease. The compound was effective in reducing the burden of early-aggregates pathology upon α-synuclein overexpression in neuroblastoma cells, as well as neutralizing both the extent and the toxicity of administered preformed fibrils. In addition, oleuropein aglycone administration was beneficial for healthspan and lifespan in animals overexpressing α-synuclein, improved motor defects, recovered dopaminergic neuronal loss, and reduced the extent of α-synuclein pathology. Finally, through molecular modelling simulations, we propose a model for the α-synuclein and oleuropein aglycone interaction, predicting a dynamic that involves early α-synuclein oligomers. Overall, our results support the neuroprotective potential of oleuropein aglycone against α-synuclein aggregation and toxicity and shed light into the molecular features of these mechanisms, suggesting that further studies should be performed to gain insight about the neuroprotective actions of this polyphenol in humans.

Keywords:  Oleuropein aglycone; Parkinson’s disease; Synucleinopathy; α-synuclein aggregation

DOI:  https://doi.org/10.1007/s12035-025-05208-6
Biochem Soc Trans. 2025 Jul 23. pii: BST20253077. [Epub ahead of print]

How does protein aggregate structure affect mechanisms of disaggregation?

YuChen Yang, Hays S Rye.

  Protein misfolding and aggregation underpin numerous pathological conditions, including Alzheimer's, Parkinson's, and Huntington's diseases. Within cells, the competition between protein folding and misfolding- driven aggregation necessitates intricate quality control systems known collectively as the proteostasis network, with molecular chaperones playing central roles. Critical gaps remain in our understanding of why certain protein aggregates are amenable to efficient chaperone-mediated disassembly, while others resist such intervention. Aggregates can be most broadly categorized into structurally ordered amyloid fibrils and more irregular amorphous clusters. Amyloid fibrils are characterized by a highly structured, cross-β-sheet architecture, and they generally display nucleation-driven growth kinetics. In contrast, amorphous aggregates form through heterogeneous interactions among partially unfolded proteins, which typically lack ordered and repeating structure but still display poorly understood, specific assembly constraints. Importantly, amorphous aggregation and amyloid formation are often linked to one another, with several different types of aggregate structures forming at the same time. The ability of molecular chaperones to remodel and disassemble aggregates is affected by aggregate size, internal structure, surface dynamics, and exposure of chaperone-binding sites. However, despite these insights, the mechanistic complexity, aggregate heterogeneity, and dynamic properties present substantial experimental and theoretical challenges. Addressing these challenges will require innovative approaches combining single-molecule biophysics, structural biology, and computational modeling to unveil universal principles governing protein aggregation and disaggregation within cellular environments.

Keywords:  amyloid; molecular chaperones; protein aggregation; protein misfolding; proteostasis

DOI:  https://doi.org/10.1042/BST20253077
Mol Brain. 2025 Jul 24. 18(1): 66

Unraveling the mystery: How autophagy deficiency in dopaminergic neurons drives human Parkinson's disease.

Sachiko Noda, Nobutaka Hattori.

  Alpha-synuclein (α-synuclein), a key component of Lewy body pathology, is a classical hallmark of Parkinson's disease. In previous studies, our group has examined dopaminergic neuron-specific Atg7 autophagy-deficient mice, observing α-synuclein aggregation in vivo. This pathological process led to dopamine neuron loss and age-related motor impairments. Further, in a recent study, we developed a new mouse model by crossing human α-synuclein bacterial artificial chromosome transgenic mice with dopaminergic neuron-specific Atg7 conditional knockout mice to further investigate these mechanisms. These model mice exhibited accelerated Lewy body-like pathology and motor dysfunction, providing additional evidence that autophagy deficiency exacerbates synuclein toxicity in vivo. This nano-review provides essential clues that autophagy deficiency in dopamine neurons may contribute to the onset of human synuclein diseases.

Keywords:  Autophagy; Dopaminergic neurons; Parkinson’s disease; Α-synuclein

DOI:  https://doi.org/10.1186/s13041-025-01235-5
Front Immunol. 2025 ;16 1615001

Protein regulatory network mediated by palmitoylation modifications in the pathological progression of Parkinson's disease: a narrative review.

Jingjing Liu, Shanshan Wang, Lei Fan, Xin Zhou, Sen Zhang, Qinglu Wang, Panpan Dong, Bo Yu.

  Palmitoylation is a reversible lipid modification regulated by palmitoyl transferases and acyl-protein thioesterases, in which palmitic acid is attached to protein cysteine residues. This modification plays a pivotal role in modulating membrane localization and protein stability, and its dysregulation is closely associated with various neurodegenerative diseases, including Parkinson's disease (PD). In PD, synaptotagmin-11, encoded by the PD risk gene SYT11, has been shown to reduce physiological α-synuclein (α-syn) tetramer formation while promoting the aggregation-prone monomeric form in a palmitoylation-dependent manner. In the context of PD, inflammation generally precedes the abnormal aggregation of α-syn and the degeneration of dopaminergic neurons (DA). Microglial activation, regarded as an inflammatory state, is facilitated by the palmitoylation-dependent localization of NLRP3 to the trans-Golgi network, which promotes the activation and expression of the NLRP3 inflammasome, leading to DA neuron loss. Additionally, the DJ-1 protein, encoded by the risk gene PARK7, and the dopamine transporter both undergo palmitoylation and may contribute to disease progression. This review summarizes the emerging link between protein palmitoylation and PD pathogenesis. Understanding the dynamic regulatory mechanisms of palmitoylation and depalmitoylation may facilitate the development of targeted therapeutic strategies for PD.

Keywords:  NLRP3 inflammasome; Parkinson’s disease; palmitoylation; synaptotagmin-11; α-synuclein

DOI:  https://doi.org/10.3389/fimmu.2025.1615001
Nat Commun. 2025 Jul 24. 16(1): 6699

Self-driving microscopy detects the onset of protein aggregation and enables intelligent Brillouin imaging.

Khalid A Ibrahim, Camille Cathala, Carlo Bevilacqua, Lely Feletti, Robert Prevedel, Hilal A Lashuel, Aleksandra Radenovic.

The process of protein aggregation, central to neurodegenerative diseases like Huntington's, is challenging to study due to its unpredictable nature and relatively rapid kinetics. Understanding its biomechanics is crucial for unraveling its role in disease progression and cellular toxicity. Brillouin microscopy offers unique advantages for studying biomechanical properties, yet is limited by slow imaging speed, complicating its use for rapid and dynamic processes like protein aggregation. To overcome these limitations, we developed a self-driving microscope that uses deep learning to predict the onset of aggregation from a single fluorescence image of soluble protein, achieving 91% accuracy. The system triggers optimized multimodal imaging when aggregation is imminent, enabling intelligent Brillouin microscopy of this dynamic biomechanical process. Furthermore, we demonstrate that by detecting mature aggregates in real time using brightfield images and a neural network, Brillouin microscopy can be used to study their biomechanical properties without the need for fluorescence labeling, minimizing phototoxicity and preserving sample health. This autonomous microscopy approach advances the study of aggregation kinetics and biomechanics in living cells, offering a powerful tool for investigating the role of protein misfolding and aggregation in neurodegeneration.

DOI: https://doi.org/10.1038/s41467-025-60912-0
ACS Chem Neurosci. 2025 Jul 18.

Tau Oligomers in Alzheimer's Disease: Modulation Effect of Osmolytes on Amplified Brain-Derived Tau Oligomers.

Sharif Arar, Md Anzarul Haque, Anas Kayed, Sheeza Khan, Nemil Bhatt, Yingxin Zhao, Rakez Kayed.

  Tau is bound to microtubules and plays a key role in their assembly and spatial organization. Under pathological conditions, tau detaches from the microtubules and develops a propensity to self-aggregate into soluble tau oligomers (TauO), paired helical filaments, and neurofibrillary tangles. Recent studies have revealed that TauO is the toxic species responsible for seeding, propagation, and development of tauopathies. Strategies that can modulate the process of TauO formation can help reduce the toxicity of TauO and stop the progression of the disease. Osmolytes are naturally occurring small-molecular-weight organic compounds, which crucially assist in the proper protein folding and thus impact the stability and solubility of proteins. Therefore, osmolytes can serve as good candidates for modulating TauO. Osmolytes cross the blood-brain barrier and act as chaperons to prevent the proteins from misfolding and aggregation. Here, we investigated the effect of different brain osmolytes against the amplified brain-derived tau oligomer (aBDTO). Our investigations have revealed that the brain osmolytes modulate the aBDTO differentially. The osmolytes sorbitol and glycerophosphocholine (GPC) displayed the potential to reduce the formation and accumulation of large aggregates by disaggregating the precursor tau oligomers into smaller assemblies with varying conformations. This may result from these osmolytes modulating the conformation of aggregated tau, which could lead to reduction in its seeding potential. However, trimethyl amine oxide (TMAO) has been found to prevent and clear out the formation of aBDTO significantly. Citrulline is less effective than TMAO and possibly affects more dimeric species. These osmolytes can become an indispensable tool for the management of Alzheimer's disease and part of hybrid therapeutic mechanisms, in addition to providing better understanding of tau oligomerization and seeding ability.

Keywords:  Alzheimer’s disease; aBDTO; circular dichroism; osmolytes; proteinase K digestion, mass spectrometry

DOI:  https://doi.org/10.1021/acschemneuro.5c00122
Front Mol Neurosci. 2025 ;18 1617771

Role of the chaperonin TCP-1 ring complex in protein aggregation and neurodegeneration.

Vanlalrinchhani Varte, Diego E Rincon-Limas.

  The chaperonin TCP-1 ring complex (TRiC), also known as chaperonin-containing TCP-1 (CCT) complex, plays a crucial role in protein folding and quality control within the cell. Comprising eight distinct subunits (CCT1 - CCT8), TRiC assists in the folding of a wide range of client proteins, ensuring their proper conformation and functionality. This mini review explores the assembly, structure, and cellular functions of TRiC and discusses its involvement in protein aggregation and neurodegenerative diseases. We emphasize the emerging role of CCT2 in modulating the formation of abnormal amyloid aggregates, including amyloid beta, tau, and polyglutamine (polyQ) deposits, which are central to the pathogenesis of various neurological conditions. Lastly, we provide evidence supporting the neuroprotective role of CCT2 in vivo and also highlight therapeutic implications and key unresolved questions in the field, offering a foundation for new research opportunities.

Keywords:  Alzheimer; CCT complex; TRiC; aggrephagy; amyloid beta; chaperonin; polyQ; tau

DOI:  https://doi.org/10.3389/fnmol.2025.1617771
Biochim Biophys Acta Mol Basis Dis. 2025 Jul 22. pii: S0925-4439(25)00339-4. [Epub ahead of print] 167991

The emerging role of eIF5A hypusination as a unique and underexplored mechanism in proteinopathies and neurological diseases.

Rohan Desai, Daniel C Lee, Maj-Linda B Selenica.

  Eukaryotic Translation Initiation Factor 5A (eIF5A) undergoes a unique post-translational modification of hypusination, converting a lysine 50 residue to hypusine (hypK50). While a few studies have investigated the role of the spermidine-hypusine-eIF5A axis in neurodegenerative diseases, including the pathological accumulation of tau and TAR DNA-binding protein 43 (TDP-43), the role of the hypusine pathway in neurological diseases remains vastly understudied. Thus, the focus of this review is highlighting emerging research on the mechanisms by which aberrant and chronic increases in hypusinated eIF5A (eIF5AhypK50) govern nucleocytoplasmic transport, stress granule dynamics, and protein aggregation to encourage further research of this pathway in multi-etiology dementia.

Keywords:  Hypusination; Neurodegeneration; Proteinopathy; TDP-43; eIF5A

DOI:  https://doi.org/10.1016/j.bbadis.2025.167991
Mol Neurobiol. 2025 Jul 24.

The Yeast Parkinson's Disease Model Exhibits An Increase in Peroxisome Number Independent of the Division Proteins Vps1 and Dnm1.

Tanveera Rounaque Sarhadi, Neha Joshi, Shirisha Nagotu.

  Aggregation of α-Synuclein is a hallmark characteristic of Parkinson's disease. Several mutant variants of α-Synuclein linked to the disease that exhibit distinct patterns of localization, aggregation dynamics, and cellular toxicity have been reported. This variability underscores the need for a detailed study of each mutant variant to understand the disease pathology better. While mitochondria have been extensively studied for their role in Parkinson's disease pathogenesis, much less is known about peroxisomes, organelles that share important functions with mitochondria. To address this, we investigated the effect of expression of WT- α-Synuclein and two disease variants A53T and A29S in yeast. Interestingly, the expression of the A53T α-Synuclein variant resulted in a significant increase in peroxisome number per cell. This increase was also observed in cells lacking peroxisome fission proteins Vps1 and Dnm1. Our data also suggests a link between the aggregation propensity of α-Synuclein and the observed effect on peroxisome number. Expression of the A29S variant of α-Synuclein and WT-α-Synuclein which exhibits a lower aggregation propensity than A53T, did not result in a similar increase in peroxisome number. In line with this, enhanced mitochondrial fragmentation was observed only upon expression of A53T α-Synuclein in WT yeast cells.

Keywords:  Mitochondria; Parkinson’s disease; Peroxisome; Protein Aggregation; Yeast; α-Synuclein

DOI:  https://doi.org/10.1007/s12035-025-05236-2
J Biol Chem. 2025 Jul 17. pii: S0021-9258(25)02324-5. [Epub ahead of print] 110474

Secretory autophagy mediates lysosomal and autophagic degradation for α-synuclein proteostasis.

Taiki Sawai, Yoshitsugu Nakamura, Shigeki Arawaka.

  Autophagy has two distinct pathways, degradation and secretion. Autophagic degradation plays a pivotal role in proteostasis. However, the role of autophagic secretion in proteostasis maintenance is not fully understood. Here, we investigate how the blockade of autophagic secretion impairs proteostasis in SH-SY5Y cells. siRNA-mediated knockdown of a modulator for autophagosome formation, ATG5, BECN1 or FIP200 inhibited autophagic flux and secretion, causing accumulation of Triton X-100-insoluble α-synuclein, which is an aggregate-prone protein responsible for neuronal loss in Parkinson's disease. The blockade of autophagic secretion by knockdown of t-SNARE SNAP23 or STX4 increased autophagic flux for p62 degradation, but these knockdowns induced enlargement and membrane damage of lysosomes as well as lysosomal dysfunction. SNAP23 or STX4 knockdown caused accumulation of Triton X-100-insoluble α-synuclein against induction of lysophagy. GBA knockdown showed lysosomal damage with the increase in autophagic secretion. RAB8A, a small GTPase regulator of polarized sorting to the plasma membrane, knockdown blocked autophagic secretion and produced lysosomal damage. SNAP23, STX4 or RAB8A knockdown further accelerated accumulation of Triton X-100-insoluble α-synuclein caused by a lysosomal protease inhibitor cocktail. Collectively, these findings suggest that SNAP23, STX4 or RAB8A knockdown blocks autophagic secretion and upregulates autophagic flux as a compensatory response to help maintain degradation. However, these knockdowns impair α-synuclein proteostasis because of lysosomal damage that they induce, counteracting compensatory effects of autophagic degradation, including lysophagy. Autophagic secretion and degradation may collaboratively form the clearance pathway required for maintaining lysosomal function by reducing the burden of aggregate-prone protein cargo.

Keywords:  Parkinson disease; autophagy; lysosome; protein secretion; proteostasis; synuclein

DOI:  https://doi.org/10.1016/j.jbc.2025.110474
ACS Chem Neurosci. 2025 Jul 23.

Investigation of Methylsulfonamide's Capability to Prevent Zn2+-Induced Aβ Peptide Aggregation Based on Zn2+ Coordination within the Zinc Binding Region of Aβ for Treatment of Alzheimer's Disease (AD).

Demet Ataman Sadık, Cemre Sare Cansız, Merve Turğut, Çağdaş Dağ, Memed Duman.

  There is no cure for Alzheimer's disease (AD) with the currently suggested therapies. Thus, designing and synthesis of new drugs for the treatment of Alzheimer's disease for safe and effective therapy have become an important task. Metal ions such as Zn2+, Cu2+, and Fe3+ are known to increase the rate of Aβ aggregation and exist in amyloid plaques at high concentrations. Aβ oligomers, whether formed on the way to amyloid fibril formation or formed off-pathway due to the interaction of Aβ monomers with Zn2+, are considered to be the most neurotoxic aggregates. Using NMR and SPR, this study reports the methylsulfonamide inhibition of Zn2+-induced Aβ1-16 dimer formation via methylsulfonamide coordination of Zn2+ within the Zn2+ binding region of Aβ, (11EVHH14) and inhibit the H14-Zn2+ coordination between the 11EVHH14 regions of two Aβ peptides, preventing their interactions and hence the Aβ dimer formation. According to the results of this study, methylsulfonamide has the potential to be used as a drug in Alzheimer's disease for the prevention of the formation of the Zn2+-induced toxic Aβ oligomers formed during Aβ aggregation.

Keywords:  Alzheimer’s disease; NMR; SPR; Zn2+ coordination; Zn2+-induced Aβ1−16 dimer formation; methylsulfonamide inhibition

DOI:  https://doi.org/10.1021/acschemneuro.5c00238
Elife. 2025 Jul 24. pii: RP95062. [Epub ahead of print]13

Rapid and inducible mislocalization of endogenous TDP43 in a novel human model of amyotrophic lateral sclerosis.

Johanna Ganssauge, Sophie Hawkins, Seema Chandramohan Namboori, Szi Kay Leung, Jonathan Mill, Akshay Bhinge.

  Transactive response DNA binding protein 43 kDa (TDP43) proteinopathy, characterized by the mislocalization and aggregation of TDP43, is a hallmark of several neurodegenerative diseases, including Amyotrophic Lateral Sclerosis (ALS). In this study, we describe the development of a new model of TDP43 proteinopathy using human induced pluripotent stem cell (iPSC)-derived neurons. Utilizing a genome engineering approach, we induced the mislocalization of endogenous TDP43 from the nucleus to the cytoplasm without mutating the TDP43 gene or using chemical stressors. Our model successfully recapitulates key early and late pathological features of TDP43 proteinopathy, including neuronal loss, reduced neurite complexity, and cytoplasmic accumulation and aggregation of TDP43. Concurrently, the loss of nuclear TDP43 leads to splicing defects, while its cytoplasmic gain adversely affects microRNA expression. Strikingly, our observations suggest that TDP43 is capable of sustaining its own mislocalization, thereby perpetuating and further aggravating the proteinopathy. This innovative model provides a valuable tool for the in-depth investigation of the consequences of TDP43 proteinopathy. It offers a clinically relevant platform that will accelerate the identification of potential therapeutic targets for the treatment of TDP43-associated neurodegenerative diseases, including sporadic ALS.

Keywords:  ALS; TDP43; genetics; genomics; human; iPSC; microRNA; neuroscience; proteinopathy; splicing

DOI:  https://doi.org/10.7554/eLife.95062
Apoptosis. 2025 Jul 23.

Targeting ASK1 signaling in neurodegeneration: molecular insights and therapeutic promise.

Nasreen Sulthana, Piyush Mittal, Ahsas Goyal, Suhas Ballal, Laxmidhar Maharana, Amita Joshi Rana, Yumna Khan, Kavita Goyal, Rakhi Mishra, Haider Ali, Gaurav Gupta, Md Sadique Hussain.

  Apoptosis signal-regulating kinase 1 (ASK1), a redox-sensitive member of the mitogen-activated protein kinase kinase kinase (MAP3K) family, is a master regulator of neuronal apoptosis as well as neuroinflammation in neurodegenerative disorders (NDs). Under oxidative and endoplasmic reticulum stress conditions, ASK1 sets off a series of pathways, ultimately leading to impairment of cellular functions and the cell's demise. The comprehensive review focuses on the diverse contributions of ASK1 to neurodegeneration driven by Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Human and animal evidence links dysregulated ASK1 signaling is related to amyloid deposition, tau hyperphosphorylation, neuroinflammation, abnormal protein folding, and subsequent neurodegeneration. ASK1 plays a role in tau hyperphosphorylation and amyloid-beta-induced neurotoxicity in AD. ASK1-mediated apoptosis of dopaminergic neurons caused by oxidative stress and aggregation of α-synuclein contributes to PD. Furthermore, ASK1 activation is associated with motor neuron degeneration in ALS related to endoplasmic reticulum stress caused by mutant SOD1. Moreover, the pathogenesis of HD involves the activation of ASK1 by the cellular stress caused by mutant huntingtin protein. ASK1 signaling potentiates inflammatory signals in MS because it is involved in demyelination and neuronal injury. Nonetheless, obstacles persist such as developing brain-targeted therapies, reducing adverse systemic effects, and defining disease-stage-specific functions of ASK1. This review aims to comprehensively examine the role of ASK1 signaling in major NDs, discuss its upstream and downstream regulatory mechanisms, and evaluate the current and emerging therapeutic strategies targeting ASK1.

Keywords:  ASK1 inhibitors; Microglia; Neurodegeneration; Neurodegenerative diseases; Neuroinflammation; Oxidative stress

DOI:  https://doi.org/10.1007/s10495-025-02148-3
Front Mol Biosci. 2025 ;12 1603364

Subtle concentration changes in zinc hold the key to fibrillation of α-synuclein: an updated insight on the micronutrient's role in prevention of neurodegenerative disorders.

Samudra Prosad Banik, Debasis Bagchi, Pradipta Banerjee, Sanjoy Chakraborty, Manashi Bagchi, Chaitali Bose, Debasmita De, Sreemoyee Saha, Sudipta Chakraborty.

  Misfolded proteins have been found to be at the core of an increasing number of cognitive ailments. α-synuclein, a resident chaperone of the neurosynaptic cleft has been implicated in a major share of these neurodegenerative diseases. Over the years, a daunting task for researchers has been the identification of the complex set of conditions which govern the Substantia nigra microenvironment for transformation of α-synuclein from a functional and grossly structureless chaperone to toxic cross-β fibrils. An abundance of Reactive Oxygen Species and a drop in pH of the solvent have been identified to be the key drivers of the fibrillation process which is initiated by Liquid-Liquid phase separation of α-synuclein droplets. Zinc is a significant micronutrient of the human body integral to the proper functioning of the nervous system as well as holistic cognitive development. Many recent studies have deciphered that metal ions including zinc facilitate the fibrillation of α-synuclein by shielding negative charges at the C terminus of the protein. Zinc preferentially binds to Asp121 at the C terminus and His50 at the N terminus to promote fibrillation. On the contrary, zinc has many protective roles to retard fibrillation of the protein at the same time. It downregulates ROS and assists chaperones which prevent non-native aggregation of α-synuclein. The ability of zinc to bind preferentially to α-synuclein coupled with the advent of ultrasensitive detection technologies such as the Surface Enhanced Raman Spectroscopy has led to the prospects of zinc-oxide nanoparticles as effective tools to probe the α-synuclein-based biomarker for early detection of protein aggregates in the body fluid. This review summarizes the significant mechanistic findings which has facilitated our understanding of the fibrillation of α-synuclein, the precise role and mechanism of zinc involved therein and the prospects of using zinc in designing efficient tools for diagnosis of Parkinson's Disease and other synucleinopathies.

Keywords:  Parkinson’s disease; ZnO nanoparticle; liquid-liquid phase separation; neurodegenerative disorders; synucleinopathies; zinc as micronutrient; α-synuclein

DOI:  https://doi.org/10.3389/fmolb.2025.1603364
Trends Neurosci. 2025 Jul 21. pii: S0166-2236(25)00138-9. [Epub ahead of print]

Triggering ferroptosis in neurodegenerative diseases.

Triet P M Nguyen, Francesca Alves, Darius J R Lane, Ashley I Bush, Scott Ayton.

  Neuronal death is a defining feature of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and motor neuron diseases, and is accordingly a priority drug target. Among the various cell death pathways, ferroptosis, a form of regulated necrosis driven by iron-dependent lipid peroxidation, has emerged as a prominent candidate underlying neurodegeneration. Despite its potential significance, putative triggers initiating lipid peroxidation cascades that lead to ferroptosis in neurodegenerative diseases remain poorly characterized. This poses significant challenges for developing targeted and disease-specific therapies. We review evidence of ferroptosis in neurodegenerative diseases and examine potential disease-relevant triggers of ferroptosis. We propose that ferroptosis, rather than being initiated by a single triggering event, emerges due to a cumulative erosion of anti-ferroptosis defense systems. This process is likely driven by context-dependent interplay between common hallmarks of neurodegenerative diseases, including neuroinflammation, protein aggregation, mitochondrial dysfunction, altered lipid metabolism, and iron accumulation.

Keywords:  iron accumulation; lipid metabolism; mitochondrial dysregulation; neuroinflammation; oxidative stress; protein aggregates

DOI:  https://doi.org/10.1016/j.tins.2025.06.008
Res Sq. 2025 Jul 15. pii: rs.3.rs-6941118. [Epub ahead of print]

Trimeric superoxide dismutase 1 antibody as a universal biomarker for ALS.

Nikolay Dokholyan, Brianna Hnath, Rachel Dokholyan, Zachary Simmons.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that leads to the loss of motor neurons, resulting in paralysis and death. Currently, there are no specific biomarkers available for diagnosing ALS. As a result, diagnosis currently relies on excluding other conditions, which forces patients to endure months or even years of uncertainty. The absence of a specific, reliable diagnostic tool has hindered both early intervention and therapeutic progress. Here we develop a novel synthetic antibody that can detect a toxic form of a known protein linked to ALS. This trimeric assembly of superoxide dismutase 1 (SOD1) is a soluble, structurally distinct oligomer that is highly toxic in cell models. The antibody selectively binds this trimer and differentiates individuals with the disease from healthy people and from those with other neurodegenerative diseases (Alzheimer's and Parkinson's disease). This breakthrough provides the first disease-specific diagnostic tool for this condition and reveals a shared pathological signature across patients, even in cases without genetic mutations. After decades without a specific diagnostic tool, this antibody signifies a long-awaited breakthrough, finally offering clinicians and researchers a reliable window into ALS pathology.

DOI: https://doi.org/10.21203/rs.3.rs-6941118/v1
J Phys Chem Lett. 2025 Jul 25. 7797-7806

Emergence of Compact Oligomers inside the Small-World Network of TDP-43 Condensates.

Huayuan Tang, Yunxiang Sun, Lei Wang, Pu Chun Ke, Feng Ding.

Liquid-liquid phase separation (LLPS) of TDP-43 mediates the formation of pathological inclusions in various neurodegenerative diseases, with the condensate structures and related amyloid aggregation remaining elusive. Here, by developing a data-driven bottom-up coarse-grained model using discrete molecular dynamics simulations, we found proteins in the condensates of TDP-43 forming a dynamic network of fluctuating sizes. While dominated by peptides engaged with a small number of peptides connected by a low number of interpeptide contacts, the condensates also contained peptides with large numbers of connections, serving as hubs of a small-world network. Importantly, peptides in these high-contact states were intertwined to form oligomers that were stable for relatively long periods inside the weakly connected network. These oligomers were likely the aggregation intermediates toward nucleation of amyloid fibrils. Therefore, this transferable coarse-grained model may serve as a powerful tool for unraveling the inner workings of LLPS and amyloid aggregation.

DOI: https://doi.org/10.1021/acs.jpclett.5c01627
Biomed Pharmacother. 2025 Jul 17. pii: S0753-3322(25)00548-7. [Epub ahead of print]190 118354

Copper metabolism and cuproptosis in Alzheimer's disease: mechanisms and therapeutic potential.

Dandan Meng, Guizhi Luo, Ping Liu.

  Alzheimer's disease (AD) is a neurodegenerative disorder with an increasing incidence rate year by year. The pathogenesis of AD is complex and closely related to protein misfolding and aggregation, neuroinflammation, oxidative stress, mitochondrial dysfunction, and other factors. Cuproptosis is a newly discovered form of programmed cell death caused by excessive intracellular copper. Unlike other known forms of cell death, it shows significant potential in the treatment of neurodegenerative diseases. Copper binds to the acylated components of the tricarboxylic acid cycle, causing protein toxicity stress, which ultimately leads to cell cuproptosis. AD is characterized by pathological features such as β-amyloid plaque formation and excessive phosphorylation of tau protein, which are closely linked to the cuproptosis mechanism. However, the specific relationship between the pathogenesis of AD and copper metabolism remains unclear. This article summarizes the metabolism of copper in the brain, the mechanisms of cuproptosis, and the pathogenesis of cuproptosis in AD, and also discusses the regulation of cuproptosis in the treatment of AD. This article provides a basis for targeted research on cuproptosis in AD.

Keywords:  Alzheimer's disease; Copper; Cuproptosis; Molecular mechanisms; Therapy

DOI:  https://doi.org/10.1016/j.biopha.2025.118354