bims-proned 2025-10-05 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2025–10–05
fifteen papers selected by
Verena Kohler, Umeå University

Synthetic chaperone based on Hsp90-Tau interaction inhibits Tau aggregation and rescues physiological Tau-Microtubule interaction.
Common Mechanism Underlying Synaptic Dysfunction Caused by Preformed Fibril-Induced Accumulation of α-Synuclein or Tau in a Culture Propagation Model.
Molecular mechanisms of amyloid inhibition: an NMR-driven framework with polyphenols as a case study.
Neurodegeneration emerges at a cellular tipping point between aggregate accumulation and removal.
Proteolytic activities of extracellular vesicles attenuate A-synuclein aggregation.
Design and application of a Tau seed amplification assay for screening inhibitors of Tau seeding.
Serial amplification of tau filaments using Alzheimer's brain homogenates and C322A or C322S recombinant tau.
Aggregation inhibitors of tau protein with anti-inflammatory potential against neurodegeneration.
Hindering Tau Fibrillization by Disrupting Transient Precursor Clusters.
Exploring Autophagy Inducing Molecules: Targeting Diverse Pathways in Alzheimer's Disease Management.
FRET-based biosensor moxCRONOS enables quantitative monitoring of macromolecular crowding in organelles and protein aggregates.
Rare bioactive tau oligomers from Alzheimer brain support both templated misfolding and fibril formation.
The Mitochondrial-Astrocyte-Neuron Triad Hypothesis in Parkinson's Disease: A Toxic Feedback Loop of Metabolism, Aggregation, and Oxidative Stress.
Large-scale visualization of α-synuclein oligomers in Parkinson's disease brain tissue.
Reduced insulin-like signaling restores motor and chemosensory neuron function in C. elegans expressing TDP-43, an ALS-associated protein.

Nat Commun. 2025 Oct 01. 16(1): 8756

Synthetic chaperone based on Hsp90-Tau interaction inhibits Tau aggregation and rescues physiological Tau-Microtubule interaction.

Davide Di Lorenzo, Nicolo Bisi, Julia Kaffy, Lisa Marie Ramirez, Markus Zweckstetter, Olivier Lequin, Irene Garfagnini, Jinghui Luo, Yvonne Hannappel, Inga Ennen, Veronica Dodero, Norbert Sewald, Maria Luisa Gelmi, Nicolo Tonali, Roland Brandt, Sandrine Ongeri.

The accumulation of intracellular aggregates of Tau protein is one main hallmark of Alzheimer's disease (AD) and is the consequence of Tau conformational changes, increased phosphorylation, and self-association to form fibrillar aggregates. This pathological process prevents the physiological interaction of Tau with microtubules to the detriment of the structural integrity of neurons. In healthy cells, aberrant protein misfolding and aggregation are counteracted by chaperone proteins whose protective capacity decreases with age. The role of the chaperone Hsp90 and the mechanism by which it can prevent Tau aggregation are controversial. In this work, the strategy of mimicking Hsp90 through the design of the β-hairpin like peptidomimetic β-Hsp90, inspired by two Hsp90/Tau interaction sequences, is presented. β-Hsp90 inhibits Tau aggregation both in vitro and in cells, restoring Tau's physiological interaction with microtubules. β-Hsp90, which interacts with the P1 region of Tau, is more effective than individual peptide sequences from the chaperone HSP90 and another β-hairpin mimic based on Tau sequences. Moreover, β-Hsp90 reduces AD-associated Aβ1-42 aggregation, offering the development of a dual inhibitor. This work paves the way for the design of new drugs targeting devastating untreated amyloid diseases, by mimicking physiological chaperones with small synthetic peptide drugs.

DOI: https://doi.org/10.1038/s41467-025-63824-1
J Neurosci. 2025 Sep 30. pii: e0394252025. [Epub ahead of print]

Common Mechanism Underlying Synaptic Dysfunction Caused by Preformed Fibril-Induced Accumulation of α-Synuclein or Tau in a Culture Propagation Model.

Dimitar Dimitrov, Sruthi Raja, Humaira Noor, Tomoyuki Takahashi.

In sporadic neurodegenerative diseases, the endogenous proteins α-synuclein in Parkinson's disease and tau in Alzheimer's disease undergo pathogenic prion-like propagation over many years, accumulating in both soluble and insoluble forms in neurons including synapses, where they impair synaptic transmission and potentially cause various neuronal symptoms. To investigate the functional outcome of such synaptic accumulation, we induced accumulation of endogenous proteins in murine and human synapses by incubating mouse (of either sex) neuronal cultures with pathogenic preformed fibrils (pffs). Two weeks after treatment with human α-synuclein or tau pff, the respective endogenous proteins accumulated in neurons including presynaptic terminals, where we also observed tubulin accumulation, suggesting microtubule over-assembly. These were not associated with mRNA upregulation and were prevented by pharmacological stimulation of autophagy. Both pffs caused accumulation of p62 in cell bodies, suggesting compromised protein degradation. pHluorin imaging in synapses indicated a marked prolongation of vesicular endocytic time, which was rescued by pharmacological depolymerization of microtubules or by the over-expression of full-length dynamin 1. Since dynamin is a high-affinity binding partner of microtubules as well as an endocytic key molecule, over-assembled microtubules can sequester dynamin, thereby inhibiting endocytosis. We conclude that pff-induced accumulation of α-synuclein or tau in presynaptic terminals can disrupt vesicle endocytosis through a common mechanism. Since endocytosis-dependent vesicle recycling is critical for maintaining neurotransmitter release, its disruption can affect the neurocircuitry operations involved, thereby causing diverse symptoms associated with neurodegenerative diseases. Thus, our data suggest a common molecular mechanism underlying synaptic dysfunctions associated with Parkinson's and Alzheimer's diseases.Significance statement The accumulation of the pathogenic proteins α-synuclein and tau drives prion-like trans-neuronal propagation and underlies distinct neurodegenerative diseases, such as Parkinson's and Alzheimer's disease. Using a synaptic culture model of protein propagation, we identified a shared mechanism of synaptic dysfunction caused by these otherwise distinct proteins. In our models, propagated α-synuclein or tau disrupt protein degradation pathways, leading to their accumulation. These accumulated proteins promote excessive microtubule assembly and sequester the key endocytic protein dynamin, eventually impairing synaptic vesicle endocytosis. This cascade results in synaptic dysfunction that could compromise neurocircuit operations critical for brain functions. Our clarification of these mechanistic steps will improve our understanding of the synaptic pathophysiology underlying diverse symptoms of distinct neurodegenerative diseases.

DOI: https://doi.org/10.1523/JNEUROSCI.0394-25.2025
Front Mol Biosci. 2025 ;12 1676927

Molecular mechanisms of amyloid inhibition: an NMR-driven framework with polyphenols as a case study.

Giacomo Zuccon, Aakriti Darnal, Edoardo Longo, Sara D'Aronco, Emanuele Boselli, Patrick Orlando, Alberto Ceccon.

  Misfolding and aggregation of intrinsically disordered proteins into amyloid fibrils are central to neurodegenerative diseases such as Parkinson's, Alzheimer's, and Huntington's. Increasing evidence suggests that transient, low-populated oligomeric intermediates, rather than mature fibrils, are key cytotoxic species. Natural polyphenols have shown promise as amyloid inhibitors, though their mechanisms of action remain unclear due to the complexity of early aggregation. This perspective explores how solution-state NMR can quantitatively assess inhibitor mechanisms. Building on recent literature elucidating the aggregation mechanisms of the huntingtin exon 1 protein (httex1), responsible for Huntington's disease, we propose a kinetic framework that integrates early reversible oligomerization with downstream fibril formation and models the impact of small-molecule binding at distinct stages of the pathway. We show that monomer sequestration and inhibition of elongation-competent nuclei produce distinct aggregation profiles, resolvable through global fitting of NMR and kinetic data. This mechanistic insight enables classification of inhibitors by target stage-monomeric, oligomeric, or fibrillar-and demonstrates how polyphenols serve as a biologically relevant case study for applying this general NMR-driven framework to the design of small-molecule amyloid inhibitors.

Keywords:  Huntington’s disease; Oligomeric Intermediates; amyloid aggregation; intrinsically disordered proteins; kinetic modeling; polyphenols; protein aggregation inhibitors; solution-state NMR spectroscopy

DOI:  https://doi.org/10.3389/fmolb.2025.1676927
bioRxiv. 2025 Sep 22. pii: 2025.09.08.674880. [Epub ahead of print]

Neurodegeneration emerges at a cellular tipping point between aggregate accumulation and removal.

Matthew W Cotton, Shriram Venkatesan, Joseph S Beckwith, Dorothea Böken, Catherine K Xu, Jonathan C Breiter, Lexie E Berkowicz, Laura Sancho Salazar, Alex Von Schulze, Ewa A Andrzejewska, Emma E Brock, Hannah L Han, Matthias M Schneider, Danny D Sahtoe, David Baker, James B Rowe, Alain Goriely, William A McEwan, Tuomas P J Knowles, Steven F Lee, Randal Halfmann, David Klenerman, Georg Meisl.

Protein aggregates are a hallmark of pathology across neurodegenerative diseases. Yet, the disconnect between molecular-level aggregation and the emergence of disease severely limits mechanistic understanding of neurodegeneration. Here, we bridge this disconnect by showing that a cellular tipping point emerges as a universal feature across diseases from the competition between aggregate accumulation and removal. We map the resulting cellular phase transition with our high-throughput live-cell assay, measuring the tipping point that separates healthy cells from those burdened with large aggregate loads. Using super-resolution imaging of brain tissue from Alzheimer's and Parkinson's disease, we quantify how the crucial balance of accumulation and removal is shifted in disease. Combined with in vitro aggregation kinetics, we then validate our framework by predicting how designed aggregation inhibitors shift the tipping point to restore cellular homeostasis. Our results provide a mechanistic framework to connect molecular-level aggregation to disease states, paving the way for a quantitative, unified understanding of neurodegeneration and enabling predictions of the complex, non-linear dynamics that govern therapeutic efficacy.

DOI: https://doi.org/10.1101/2025.09.08.674880
NPJ Parkinsons Dis. 2025 Sep 29. 11(1): 277

Proteolytic activities of extracellular vesicles attenuate A-synuclein aggregation.

Kostas Vekrellis, Agaristi Lamprokostopoulou, Katerina Melachroinou, Marianna Kokoli, Eleni Zingkou, Marina Skarveli, Asimina Kolianou, Martina Samiotaki, Georgia Sotiropoulou.

Extracellular vesicles (EVs) are nano-sized lipid vesicles released into the extracellular space. We investigated the role of mouse brain-derived EVs in α-synuclein (α-syn) degradation and pathology transmission. Using sucrose gradient isolation and biochemical characterization, we found that EVs harbor active proteases that cleave both monomeric α-syn and pre-formed fibrils (PFFs). Protease activity and inhibitor profiling identified cathepsins B and S as key enzymes mediating this cleavage. EV-mediated proteolysis reduced the seeding capacity of α-syn PFFs in vitro and in vivo, whereas protease inhibition enhanced aggregation. Proteomic analysis revealed a restricted protease repertoire within EV cargo. Our findings suggest that EVs regulate extracellular α-syn levels via proteolysis, thereby modulating its prion-like spreading potential. We suggest that EVs represent a novel post-translational mechanism to regulate the levels of extracellular α-syn and may thus affect the spreading of α-syn pathology. Targeting this proteolytic capacity may offer new therapeutic interventions for mitigating synucleinopathies.

DOI: https://doi.org/10.1038/s41531-025-01122-9
Alzheimers Res Ther. 2025 Sep 30. 17(1): 214

Design and application of a Tau seed amplification assay for screening inhibitors of Tau seeding.

Damian Gorski, Haley Evans, Tyler Allison, Carla Barria, Danielle Harrison, Victor Banerjee, Nicolas Mendez, Mohammad Shahnawaz, Sanne Kaalund, Jonas Folke, Susana Aznar, Paul Schultz, Fei Wang, Claudio Soto.

   BACKGROUND: Tau protein aggregates are a key pathological hallmark of Alzheimer's disease (AD) and are closely associated with cognitive decline and neurodegeneration. It is proposed that tau aggregates faithfully propagate throughout the brain by self-templating their disease-associated conformation onto natively-folded tau monomers, thereby inducing their aggregation and incorporation into growing fibrils. As such, the inhibition or modulation of tau seeding and aggregation represents a viable therapeutic strategy for AD and other tauopathies.
METHODS: We have recently developed seed amplification assays (SAA) for the detection and amplification of small quantities of misfolded protein aggregates in various neurodegenerative diseases. In this article, we adapted the SAA technology to amplify the process of tau aggregation and seeding in AD brain samples. Using the Tau-SAA we screened two chemical libraries: one comprising over 20 suspected aggregation inhibitors and the other comprising over 200 FDA-approved, blood-brain barrier-permeable compounds from a commercial chemical library. We also performed secondary in vitro assays to confirm the activity of selected hits as well as determining the IC50 of the most active compounds.
RESULTS: Our Tau-SAA detects the presence of tau seeds even after a 100-million-fold dilution of the initial inoculum. Examination of 26 postmortem brain samples from AD and control cases confirmed that our assay is specific for AD brain tau seeds. Screening of 220 compounds showed that approximately 57% of suspected aggregation inhibitors and ~ 3% of CNS-penetrant compounds inhibited over 75% of AD brain-templated tau aggregation.
CONCLUSIONS: In conclusion, our data suggests that Tau-SAA readily detects the presence of tau seeds in AD brains but not in controls, and that by amplifying AD brain tau seeds, the assay may serve as a valuable primary drug screening platform.

Keywords:  Alzheimer’s disease; Drug screening; Misfolded protein aggregates; Seed amplification assay; Tau; Therapeutics

DOI:  https://doi.org/10.1186/s13195-025-01855-y
FEBS Lett. 2025 Sep 30.

Serial amplification of tau filaments using Alzheimer's brain homogenates and C322A or C322S recombinant tau.

Alessia Santambrogio, Sofia Lövestam, Michael A Metrick, Thomas Löhr, Peifeng Xu, Nicholas C T Gallagher, Bernardino Ghetti, Byron Caughey, Sjors H W Scheres, Michele Vendruscolo.

  The assembly of tau into amyloid filaments is a hallmark of Alzheimer's disease (AD) and other tauopathies. Cryo-EM revealed the existence of disease-specific tau folds, which are challenging to replicate in vitro. We studied three full-length recombinant 0N3R tau forms (the wild-type and the C322A and C322S variants) using an RT-QuIC assay with brain homogenate seeding. C322A tau formed filaments resembling AD paired helical filaments (PHFs) but with a more open C-shaped core. C322S tau yielded structurally distinct filaments with an ordered C-terminal region. Both mutants seeded further aggregation, whereas the wild-type showed poor reproducibility and mainly unfolded aggregates. These results highlight the importance of optimised conditions to produce disease-relevant tau filaments and aid the development of targeted therapies. Impact statement We investigated the seeded assembly of 0N3R tau and its two mutational variants C322A and C322S, using Alzheimer's disease brain homogenates in a real-time quaking-induced conversion (RT-QuIC) assay. The C322A variant formed filaments partially resembling the AD PHF structure, showing the importance of optimised conditions to produce disease-relevant tau filaments.

Keywords:  Alzheimer's disease; RT‐QuIC; cryo‐EM; disease‐relevant filament polymorphism; protein aggregation; tau

DOI:  https://doi.org/10.1002/1873-3468.70141
Bioorg Chem. 2025 Sep 24. pii: S0045-2068(25)00910-1. [Epub ahead of print]165 109030

Aggregation inhibitors of tau protein with anti-inflammatory potential against neurodegeneration.

Bilal Nehmeh, Alia Khalil, Jana Tfaili, Wissam H Faour, Elias Akoury.

  Alzheimer's disease (AD) is characterized by two pathological hallmarks: extracellular β-amyloid plaques and intracellular neurofibrillary tangles (NFTs) formed by aggregated Tau protein. Ongoing research focuses on identifying inhibitors that either block Tau aggregation or destabilize pre-formed fibrils. In this study, we evaluated derivatives of Rhodanine (RDN), Anthraquinone (AQ), Phenylaminopyrimidine (PhNH2), Phenylthiazol hydrazide (PTH) and Benzothiazole (BZT) as potential modulators of Tau aggregation. We synthesized target compounds using Pd- and Cu-catalyzed coupling reactions and confirmed their structures via NMR spectroscopy. Thioflavin T fluorescence assays and 1H15N Heteronuclear Single Quantum Coherence (HSQC) NMR experiments demonstrated that PhNH2 and PTH effectively inhibited Tau polymerization by interacting with key hexapeptide motifs. Additionally, AQ, RDN, and PhNH2 reduced iNOS and COX-2 expression in LPS-stimulated monocytes, underscoring their anti-inflammatory activity. These findings suggest PhNH2 and PTH as promising candidates for modulating Tau aggregation, with PhNH2 exhibiting dual anti-aggregation and anti-inflammatory properties.

Keywords:  Aggregation inhibitors; Alzheimer's disease; Inflammation; Intrinsically disordered proteins; Tau protein

DOI:  https://doi.org/10.1016/j.bioorg.2025.109030
Neurosci Res. 2025 Oct 01. pii: S0168-0102(25)00151-8. [Epub ahead of print] 104968

Hindering Tau Fibrillization by Disrupting Transient Precursor Clusters.

Tomomi Takahashi, Takashi Nonaka, Reiko Ohtani, Masato Hasegawa, Yukiko Hori, Taisuke Tomita, Rei Kurita.

  Tau protein, a central player in Alzheimer's disease (AD), exhibits cytotoxicity upon ﬁbril formation. Understanding the early stages of tau ﬁbrillization is therefore critical for the development of eﬀective thera- peutics. Previous work [Rasmussen. et. al, J. Mol. Biol., 2023] reported the rapid formation of Thioﬂavin T (ThT)-inactive clusters upon mixing tau with anionic polymers, yet the functional role of these clusters remained unclear. Here, we demonstrate that these transient clusters act as obligatory precursors in the ﬁbrillization pathway. Using small-angle X-ray scattering (SAXS) and ThT ﬂuorescence, we show that disrupting the clusters via NaCl addition hinders ﬁbril formation, highlighting their reversible and targetable nature. This behavior is analogous to polymer crystallization, in which disordered chains undergo structural ordering through intermediate precursor states. We propose that similar physical principles underlie the aggregation of other intrinsically disordered pro- teins such as α-synuclein.

Keywords:  AD; precursor; tau protein; ﬁbril

DOI:  https://doi.org/10.1016/j.neures.2025.104968
Med Res Rev. 2025 Sep 29.

Exploring Autophagy Inducing Molecules: Targeting Diverse Pathways in Alzheimer's Disease Management.

Baljinder Singh, Shubham Mahajan, Sadikalmahdi Abdella, Rehan Khan, Sanjay Garg.

  Neurodegenerative disorders, including Alzheimer's disease (AD), impose a significant burden on society due to their progressive nature and the associated healthcare costs. Autophagy, a vital cellular degradation process, has emerged as a promising therapeutic target in these disorders. This review aims to provide a comprehensive overview of autophagy's role in neurodegenerative diseases, focusing on AD. The pathogenesis of AD involves the accumulation of misfolded proteins, such as beta-amyloid (Aβ) and tau, leading to neuronal dysfunction and cognitive impairment. Autophagy can be crucial in clearing these protein aggregates and maintaining cellular homeostasis. Nevertheless, autophagic dysregulation and mitochondrial dysfunction contribute to further progression of neurodegeneration. Furthermore, recent studies have demonstrated the therapeutic potential of several plant-based phytoconstituents and repurposed molecules that modulate autophagy. These compounds target both mTOR-dependent and independent pathways, highlighting their potential to alleviate disease pathology. This review aims to pave the way for future research and development in this field.

Keywords:  autophagy inducers; neurodegenerative disorders; phytoconstituents; repurposed molecules; senile dementia

DOI:  https://doi.org/10.1002/med.70013
J Biochem. 2025 Sep 30. pii: mvaf056. [Epub ahead of print]

FRET-based biosensor moxCRONOS enables quantitative monitoring of macromolecular crowding in organelles and protein aggregates.

Yurina Nakajima, Hiroaki Suzuki, Tamami Miyagi, Kohsuke Kanekura.

  Macromolecular crowding is a fundamental property of the intracellular environment that influences protein folding, enzymatic activity, and phase behavior. Disruptions to the homeostasis of macromolecular crowding can drive pathological processes, such as aberrant liquid-liquid phase separation and protein aggregation, which are central features of several neurodegenerative diseases. However, tools for quantifying crowding and aggregation remain limited. Here, we describe moxCRONOS, a Förster resonance energy transfer (FRET)-based biosensor that enables the quantitative measurement of macromolecular crowding and protein condensation. moxCRONOS retains the optical properties of the original CRONOS sensor but offers enhanced stability in oxidative environments, such as within the endoplasmic reticulum or under sodium arsenite treatment, allowing for direct comparison of crowding levels across organelles regardless of redox conditions. Moreover, when fused to dipeptide repeat proteins associated with C9ORF72-linked neurodegeneration, moxCRONOS detects aggregation-prone states-especially in cells expressing glycine-alanine (GA) repeats. Using fluorescence-activated cell sorting, we achieved sensitive and quantitative detection of heterogeneous high-FRET cell populations containing GA aggregates. FRET signal intensity increased upon treatment with a molecular crowding agent or a proteasome inhibitor. These findings establish moxCRONOS as a versatile biosensor for investigating both physiological macromolecular crowding and pathological protein aggregation, with significant potential for disease modeling and therapeutic screening.

Keywords:  Biosensor; FRET; LLPS; Macromolecular crowding; Protein aggregation

DOI:  https://doi.org/10.1093/jb/mvaf056
bioRxiv. 2025 Sep 25. pii: 2025.09.24.678227. [Epub ahead of print]

Rare bioactive tau oligomers from Alzheimer brain support both templated misfolding and fibril formation.

Noé Quittot, Dhanush Sivasankaran, Dorothea Boeken, Yu Chen, Joshua E Chun, Anne Wiedmer, Victoria Derosla, Mariana B M S Martins, Forest A Brooks, Georg Meisl, Matthew Cotton, Durga G Arumuganainar, Theresa Connors, Alexandra Melloni, Mathew Frosch, Derek Oakley, Lee Makowski, Meni Wanunu, David Klenerman, Bradley T Hyman.

The accumulation of hyperphosphorylated tau aggregates is a hallmark of Alzheimer's disease (AD). In addition to long-recognized tau deposits in neurofibrillary tangles, recent studies suggest that diffusible, aqueous soluble (High Molecular Weight, or HMW) species are also bioactive, i.e., able to seed templated misfolding. The characteristics of the diffusible misfolded proteins are largely unknown, and their relationship to classical fibrillar structures is unclear. Using sequential size exclusion and anion exchange chromatography, we fractionated the HMW tau population and identified multiple subspecies varying in retention properties. The subspecies that elute early from the size column, and are retained on the anion exchange column are seed competent, whereas the other soluble fractions are not. Biophysical analyses using super resolution, atomic force, and immunogold electron microscopy confirmed that the size and conformation of both bioactive and non-bioactive tau oligomers are similar, with dimers, trimers, and tetramers predominating. The presence of surface phosphorylations, as detected by recently developed single molecule array (SIMOA) analyses, correlates with seeding capacity. Single bioactive tau oligomers at fMol concentrations can induce seeding and templated misfolding in a reporter cell. The bioactive species can alternatively support aggregation of a truncated repeat domain tau construct into thioflavin T positive fibrils in a real-time quacking-induced conversion (RT-QuIC) assay, whereas full length recombinant tau yields oligomers. These findings provide structural insights into bioactive oligomeric tau species, emphasize the small concentrations necessary for bioactivity, and highlight the possibility that, under different conditions, they can seed either oligomeric or fibrillar structures.

DOI: https://doi.org/10.1101/2025.09.24.678227
Neurochem Res. 2025 Oct 04. 50(5): 317

The Mitochondrial-Astrocyte-Neuron Triad Hypothesis in Parkinson's Disease: A Toxic Feedback Loop of Metabolism, Aggregation, and Oxidative Stress.

Vaishali Walecha, Pratibha M Luthra.

  The medical field has spent many years investigating Parkinson's disease (PD), primarily focusing on its main pathogenic feature, dopaminergic neuronal degeneration. Recent studies indicate that PD develops through a complex pathogenic model that links mitochondria to astrocytes and neurons, creating a destructive metabolic loop, a protein aggregation cycle, and oxidative stress. This review examines how mitochondria integrate with astrocytes and neurons in the "triad hypothesis," offering a multifaceted perspective on PD progression. Despite being previously overlooked, we have observed that astrocytic mitochondria play a central role in maintaining neuroprotection and homeostasis. Given that, dysfunctional mitochondria in astrocytes and neurons lead to metabolic failure, compromised glutamate regulation, while also enhancing α-synuclein aggregation, amplifying neuroinflammation, ferroptotic vulnerability and oxidative stress. Henceforth, this report discusses current insights into astrocyte-neuron metabolic coupling, mitochondrial quality control, and lipid redox imbalance, highlighting the role of astrocytic mitochondria as a strong therapeutic strategy. We discuss experimental and translational approaches that aim to restore triad integrity, including mitophagy enhancement, metabolic reprogramming, mitochondrial transfer, and astrocyte-to-neuron reprogramming. By positioning astrocytic mitochondria at the core of PD pathogenesis, this review advocates novel interventions focused on glial metabolic resilience. This integrated approach addresses three major pathogenic axes. It offers promising potential for disease modification and developing effective therapeutics beyond symptomatic dopamine replacement to correct neurodegenerative conditions.

Keywords:  Astrocytic mitochondria; Calcium signalling; Ferroptosis; Mitochondrial dysfunction; Mitochondrial transfer; Neurodegeneration; Neuroinflammation; Neuron-astrocyte interaction; Oxidative stress; Parkinson’s disease (PD); α-Synuclein aggregation

DOI:  https://doi.org/10.1007/s11064-025-04559-9
Nat Biomed Eng. 2025 Oct 01.

Large-scale visualization of α-synuclein oligomers in Parkinson's disease brain tissue.

Rebecca Andrews, Bin Fu, Christina E Toomey, Jonathan C Breiter, Joanne Lachica, Joseph S Beckwith, Ru Tian, Emma E Brock, Lisa-Maria Needham, Gregory J Chant, Camille Loiseau, Angèle Deconfin, Kenza Baspin, Rebeka Popovic, James Evans, Yen Goh, Begüm Kurt, Lenart Senicar, Marisa Edmonds, Tim Bartels, Nora Bengoa-Vergniory, Peter J Magill, Zane Jaunmuktane, Oliver J Freeman, Benjamin J M Taylor, John Hardy, Tammaryn Lashley, Mina Ryten, Michele Vendruscolo, Nicholas W Wood, Lucien E Weiss, Sonia Gandhi, Steven F Lee.

Parkinson's disease (PD) is a neurodegenerative condition characterized by the presence of intraneuronal aggregates containing fibrillar ɑ-synuclein known as Lewy bodies. These large end-stage species are formed by smaller soluble protein nanoscale assemblies, often termed oligomers, which are proposed as early drivers of pathogenesis. Until now, this hypothesis has remained controversial, at least in part because it has not been possible to directly visualize nanoscale assemblies in human brain tissue. Here we present Advanced Sensing of Aggregates-Parkinson's Disease, an imaging method to generate large-scale α-synuclein aggregate maps in post-mortem human brain tissue. We combined autofluorescence suppression with single-molecule fluorescence microscopy, which together enable the detection of nanoscale α-synuclein aggregates. To demonstrate the use of this platform, we analysed ~1.2 million nanoscale aggregates from the anterior cingulate cortex in human post-mortem brain samples from patients with PD and healthy controls. Our data reveal a disease-specific shift in a subpopulation of nanoscale assemblies that represent an early feature of the proteinopathy that underlies PD. We anticipate that quantitative information about this distribution provided by Advanced Sensing of Aggregates-Parkinson's Disease will enable mechanistic studies to reveal the pathological processes caused by α-synuclein aggregation.

DOI: https://doi.org/10.1038/s41551-025-01496-4
MicroPubl Biol. 2025 ;2025

Reduced insulin-like signaling restores motor and chemosensory neuron function in C. elegans expressing TDP-43, an ALS-associated protein.

Vincent Lotesto, Cindy Voisine.

TAR DNA-binding Protein 43 (TDP-43) is linked to the pathology of neurodegenerative diseases. We used the roundworm Caenorhabditis elegans to examine the neurotoxic impact of the pan-neuronal expression of wild-type human TDP-43 (hTDP-43) fused to a yellow fluorescent protein. Using the daf-2 ( e1370 ) mutant allele, we sought to determine whether activating cellular stress responses in the insulin-like signaling (ILS) pathway could restore neuronal function in hTDP-43 expressing C. elegans . Using well characterized behavioral assays, our data show that manipulating the ILS pathway significantly improves functionality of motor and chemosensory neurons in animals expressing hTDP-43.

DOI: https://doi.org/10.17912/micropub.biology.001788