bims-axbals Biomed News
on Axonal biology and ALS
Issue of 2025–10–26
nineteen papers selected by
TJ Krzystek
  1. Emerging roles of primary cilia in the pathogenesis of amyotrophic lateral sclerosis.
  2. LRRK2 kinase-mediated accumulation of lysosome-associated phospho-Rabs in tauopathies and synucleinopathies.
  3. TDP-43 nuclear loss in FTD/ALS causes widespread alternative polyadenylation changes.
  4. Endoplasmic reticulum in the axon: Insights into structural dynamics and implications in neurodegeneration.
  5. Protocol for generating a human iPSC-derived tri-culture model to study interactions between neurons, astrocytes, and microglia.
  6. ITCH regulates Golgi integrity and proteotoxicity in neurodegeneration.
  7. On the potential roles of TDP-43 in the formation of membraneless organelles and their transformation into toxic aggregates.
  8. Myosin VI controls localization of golgi satellites at active presynaptic boutons.
  9. A paradoxical role of autophagy: promoting protein aggregates and hindering rejuvenation in a Caenorhabditis elegans L1 arrest model.
  10. Enhanced hybridization-proximity labeling discovers protein interactomes of single RNA molecules.
  11. TDP-43 loss induces cryptic polyadenylation in ALS/FTD.
  12. Quantifying subpercent nuclear TDP-43 loss in cells and ALS cortex using junction-specific cryptic exon RT-qPCR.
  13. ATG9 assists lipid replenishment for lysosome membrane repair.
  14. Mitochondrial calcium overload is the trigger for carbon monoxide neurotoxicity.
  15. Human iPSC-Based in Vitro Cardiovascular Tissue Models for Drug Screening Applications.
  16. Development of a robust, physiologically relevant neuronal tau aggregation assay for tau-related drug discovery.
  17. TMEM175 does not function as a proton-selective ion channel to prevent lysosomal over-acidification.
  18. Beyond prion-like spreading in neurodegenerative disease.
  19. Actin cytoskeleton protection by the formin-mediated safety valve.
  1. Front Neurosci. 2025 ;19 1688839
    Emerging roles of primary cilia in the pathogenesis of amyotrophic lateral sclerosis.
    Hisashi Takahashi, Takashi Kasai, Aya Miyagawa-Hayashino, Tomoyuki Ohara.
      Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease primarily affecting motor neurons, for which effective disease-modifying therapies remain elusive. Primary cilia are solitary microtubule-based organelles critical for signal transduction and have recently been implicated in ALS pathogenesis. In this review, we provide a basic overview of the structure, dynamics, and functions of primary cilia, particularly in the brain. We highlight accumulating evidence from ALS models showing altered ciliary structure and function and explore how mutations in ALS-associated genes such as NEK1, C21orf2, and C9orf72 disrupt ciliogenesis and ciliary signaling. Moreover, we examine the interplays between primary cilia dysfunction and known ALS-related mechanisms, including loss of proteostasis, abnormal RNA metabolism, microtubule dysfunction, neuroinflammation, and mitochondrial dysfunction. Collectively, the evidence suggests a bidirectional relationship in which ciliary impairment and ALS pathomechanisms reinforce one another in a vicious cycle. We further discuss emerging therapeutic strategies targeting ciliary function, as well as the potential for primary cilia as novel clinical applications. Our review highlights primary cilia as a previously underappreciated yet potentially important component of ALS biology, offering novel insights into disease mechanisms and future therapeutic development.
    Keywords:  C21orf2; C9orf72; NEK1; aging; amyotrophic lateral sclerosis; ciliopathy; neurodegeneration; primary cilia
    DOI:  https://doi.org/10.3389/fnins.2025.1688839
  2. Acta Neuropathol. 2025 Oct 23. 150(1): 44
    LRRK2 kinase-mediated accumulation of lysosome-associated phospho-Rabs in tauopathies and synucleinopathies.
    Silas A Buck, Tuyana Malankhanova, Samuel Strader, Eileen B Ma, Sarah Yim, Harrison W Pratt, John Ervin, Edward B Lee, Shih-Hsiu J Wang, Todd J Cohen, Andrew B West, Laurie H Sanders.
      Parkinson's disease (PD) pathogenic mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with endolysosomal dysfunction across cell types, and carriers of LRRK2 mutations variably present with phosphorylated tau and α-synuclein deposits in post-mortem analysis. LRRK2 mutations increase the phosphorylation of Rab substrates including Rab12 and Rab10. Rab12 and Rab10 are expressed in neuronal and non-neuronal cells with localization to membranes in the endolysosomal compartment, and lysosomal stress activates LRRK2 phosphorylation of Rabs. In this study, using antibodies directed to the LRRK2-mediated phosphorylation sites on Rab12 at amino acid Ser106 (pS106-Rab12) and Rab10 at amino acid Thr73 (pT73-Rab10), we test whether aberrant LRRK2 phosphorylation is associated with tau and/or α-synuclein pathology across clinically distinct neurodegenerative diseases. Analysis of brain tissue lysates and immunohistochemistry of pathology-susceptible brain regions demonstrate that pS106-Rab12 levels are increased in Alzheimer's disease (AD) and Lewy body disease (LBD), including PD with and without G2019S LRRK2 mutation. At early pathological stages, phosphorylated Rab12 localizes to granulovacuolar degeneration bodies (GVBs), which are thought to be active lysosomal-like structures, in neurons. pS106-Rab12-positive GVBs accumulate with pathological tau across brain tissues in AD and LBD, and in G2019S LRRK2 mutation carriers. In a mouse model of tauopathy, pS106-Rab12 localizes to GVBs during early tau deposition in an age-dependent manner. While GVBs are largely absent in neurons with mature protein pathology, subsets of both tau and α-synuclein inclusions appear to incorporate pS106-Rab12 at later pathological stages. Further, pS106-Rab12 labels GVBs in neurons and shows co-pathology with tau inclusions in primary tauopathies including Pick's disease, progressive supranuclear palsy, and corticobasal degeneration. Finally, pT73-Rab10 is elevated and localizes to GVBs, but not tau and α-synuclein inclusions, in AD and LBD, including G2019S LRRK2 mutation carriers. These results implicate LRRK2 kinase activity and Rab phosphorylation in endolysosomal dysfunction in tau- and α-synuclein-associated neurodegenerative diseases.
    Keywords:  Alzheimer’s disease; LRRK2; Parkinson’s disease; Rab12; Synuclein; Tau
    DOI:  https://doi.org/10.1007/s00401-025-02951-x
  3. Nat Neurosci. 2025 Oct 21.
    TDP-43 nuclear loss in FTD/ALS causes widespread alternative polyadenylation changes.
    Yi Zeng, Anastasiia Lovchykova, Tetsuya Akiyama, Stephanie L Rayner, Vidhya Maheswari Jawahar, Chang Liu, Odilia Sianto, Caiwei Guo, Anna Calliari, Mercedes Prudencio, Dennis W Dickson, Leonard Petrucelli, Aaron D Gitler.
      In frontotemporal dementia and amyotrophic lateral sclerosis, the RNA-binding protein TDP-43 is depleted from the nucleus of neurons in the brain and spinal cord. A key function of TDP-43 has emerged as a repressor of cryptic exon inclusion during pre-mRNA splicing, but a role for TDP-43 in other RNA-processing events remains unresolved. Here we show that loss of TDP-43 from neuronal nuclei of human brain and disease-causing mutations in TDP-43 are associated with widespread changes in alternative polyadenylation (APA). Using high-resolution polyadenylation site mapping, we comprehensively defined TDP-43-regulated APA events in human stem cell-derived neurons and found that both the strength and position of TDP-43 binding influence polyA site usage. APA events caused by loss of TDP-43 impact expression of disease-relevant genes (for example, SFPQ, NEFL and TMEM106B). These findings provide evidence that, in addition to cryptic exon inclusion, APA changes are a new facet of TDP-43 pathology.
    DOI:  https://doi.org/10.1038/s41593-025-02049-3
  4. Neurobiol Dis. 2025 Oct 22. pii: S0969-9961(25)00369-9. [Epub ahead of print] 107152
    Endoplasmic reticulum in the axon: Insights into structural dynamics and implications in neurodegeneration.
    Trang Dai Vu, Hyun Sung.
      The endoplasmic reticulum (ER) is an interconnected and highly dynamic organelle essential for multiple cellular functions. In neurons, the ER extends into axons, where it plays a pivotal role in maintaining neuronal polarity. The unique structural and dynamic adaptations of the axonal ER enable it to meet the specialized demands of neurons, ranging from compartmentalized physiological regulation to long-distance intracellular communication. Recent studies have shown that axonal ER supports the regulation of organelle remodeling and trafficking in a spatiotemporal manner, processes that become compromised in aged neurons. Moreover, disruptions in the structure and dynamics of the axonal ER have increasingly become associated with neurodegenerative diseases, including hereditary spastic paraplegia, amyotrophic lateral sclerosis, and peripheral neuropathies. This review synthesizes current knowledge of axonal ER biology, highlighting its structural and dynamic characteristics, its impact on organelle arrangement and distribution, and its pathological implications in neurodegeneration. By consolidating recent advances, this review outlines emerging questions and future directions in axonal ER research, a field gaining recognition for its contribution to neuronal dysfunction and neurodegenerative pathomechanisms.
    Keywords:  Axon; Axonal transport; ER-shaping proteins; Endoplasmic reticulum; Membrane contact sites; Neurodegenerative diseases; Organelle dynamics
    DOI:  https://doi.org/10.1016/j.nbd.2025.107152
  5. STAR Protoc. 2025 Oct 22. pii: S2666-1667(25)00558-1. [Epub ahead of print]6(4): 104152
    Protocol for generating a human iPSC-derived tri-culture model to study interactions between neurons, astrocytes, and microglia.
    Alexandra M Lish, Paige C Galle, Gwendolyn A Orme, Nancy Ashour, Sarah E Heuer, Annabel J Curle, Christina R Muratore, Tracy L Young-Pearse.
      Human induced pluripotent stem cell (hiPSC) models enable disease modeling and drug screening, but standardized methods for multi-lineage co-culture remain limited. Here, we present a cryopreservation-compatible tri-culture system of neurons, astrocytes, and microglia. We describe steps for transducing induced pluripotent stem cells (iPSCs) with cell type-specific factors, generating intermediate cryopreserved stocks, differentiating each cell population, and assembling them into tri-culture. This protocol provides a reproducible platform to study dynamic interactions between human brain cells in a physiologically relevant environment. For complete details on the use and execution of this protocol, please refer to Lish et al.1,2.
    Keywords:  Immunology; Neuroscience; cell Biology; cell culture; cell differentiation; stem cells
    DOI:  https://doi.org/10.1016/j.xpro.2025.104152
  6. Sci Adv. 2025 Oct 24. 11(43): eado4330
    ITCH regulates Golgi integrity and proteotoxicity in neurodegeneration.
    Qiwang Xiang, Yuning Lu, Hongjin Wang, Hao Chen, Peng Chen, Xiaofeng Zhao, Larissa Cortes Morales, Yiwei Yang, Junqin Yang, Tao Zhang, Jiou Wang.
      Golgi fragmentation is an early and common feature of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD). However, whether a shared mechanism drives Golgi fragmentation across different neurodegenerative conditions remains unclear. Here, we identify the E3 ubiquitin-protein ligase Itchy homolog (ITCH) as a key regulator of proteotoxicity through its role in inducing Golgi fragmentation. Disease-associated accumulation of ITCH promotes fragmentation of both the cis- and trans-Golgi networks, disrupting protein sorting and impairing lysosomal functions. The ITCH-dependent lysosomal dysfunction compromises the clearance of misfolded proteins associated with several neurodegenerative diseases. Inhibition of ITCH protects against proteotoxicity in both mammalian neurons and Drosophila models of neurodegeneration. The accumulation of ITCH in patients with ALS and AD is attributed to up-regulation of the ubiquitin-specific protease USP11, which deubiquitinates and stabilizes ITCH. These results uncover a pathogenic pathway regulating Golgi integrity and contributing to the development of neurodegenerative diseases.
    DOI:  https://doi.org/10.1126/sciadv.ado4330
  7. Biochem Biophys Res Commun. 2025 Oct 15. pii: S0006-291X(25)01524-4. [Epub ahead of print]788 152808
    On the potential roles of TDP-43 in the formation of membraneless organelles and their transformation into toxic aggregates.
    Olga S Sergeeva, Margarita V Neklesova, Vladislav A Reushev, Alexey V Artemov, Irina M Kuznetsova, Konstantin K Turoverov, Vladimir N Uversky, Alexander V Fonin.
      Trans-activation response (TAR) DNA-binding protein 43 (TDP-43) is an RNA-binding protein involved in the processing, transport, and regulation of mRNA translation. It is distributed in many tissues, including the brain, where it is found mainly in hippocampal neurons. Abnormal localization, hyperphosphorylation, and aggregation of TDP-43 are pathological signs of a group of neurodegenerative diseases known as TDP-43 proteinopathies. Despite the growing understanding of the physiological role of TDP-43 in ensuring neuronal plasticity and the formation of long-term memory, to date, there is no comprehensive data on the molecular and cellular mechanisms of the transformation of functional membraneless organelles (MLOs) containing TDP-43 into toxic aggregates and the pathogenesis of associated diseases, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This review is devoted to highlighting the role of MLOs in the formation of irreversible aggregates, the role of TDP-43 in the formation of MLOs and their relationship with pathological forms of TDP-43, most often found in people suffering from neurodegenerative diseases.
    DOI:  https://doi.org/10.1016/j.bbrc.2025.152808
  8. Cell Mol Life Sci. 2025 Oct 21. 82(1): 357
    Myosin VI controls localization of golgi satellites at active presynaptic boutons.
    Nathalie Hertrich, Yuhao Han, Nathanael Doil, Dimitra Ranti, Britta Eickholt, Anja Konietzny, Marina Mikhaylova.
      Neurons, as long-lived non-dividing cells with complex morphology, depend on a highly elaborate secretory trafficking system which enables a constant turnover of proteins and membranes. Previously, it was shown that simplified, Golgi-related structures called Golgi satellites (GS) are present in the dendrites of primary hippocampal neurons. These organelles are distinct from the somatic Golgi complex and are involved in de novo glycosylation and local forward trafficking of membrane proteins. However, the question of whether GS are also targeted to the axons of principal neurons remained unanswered. In this study, we investigated the subcellular distribution of GS in adult hippocampal neurons. Our findings showed that GS are present all along the axon, extending to the distal tips of the growth cone. Similar to dendritic GS, the axonal organelles are labeled by the same GS markers and are capable of mature glycosylation. Live imaging experiments revealed the presence of both mobile and immobile GS in the axon, and that the switch between active transport and stalling of GS was modulated by neuronal firing. We found that GS frequently pause at en passant synapses and remain stationary for longer time periods at activated pre-synaptic boutons. This behavior is dependent on the actin cytoskeleton and the actin-based motor protein myosin VI. Overall, our study demonstrates that neuronal activity can dynamically regulate the positioning of GS in the axon, shedding light on the intricate mechanisms underlying organelle trafficking in neurons.
    Keywords:  Axon; Golgi satellites; Myosin VI; Organelle transport; Synapse, glycosylation
    DOI:  https://doi.org/10.1007/s00018-025-05896-2
  9. Autophagy. 2025 Nov;21(11): 2311-2312
    A paradoxical role of autophagy: promoting protein aggregates and hindering rejuvenation in a Caenorhabditis elegans L1 arrest model.
    Yuxiang Huang, Daniel J Klionsky.
      Macroautophagy (hereafter referred to as autophagy) is widely recognized as a central pathway for the clearance of protein aggregates and the maintenance of proteostasis. However, a recent study by Murley et al. challenges this conventional view. Using a Caenorhabditis elegans L1 arrest aging model, the authors found that autophagy activation impedes rejuvenation by promoting the accumulation of intra- 10 lysosomal protein aggregates and inducing lysosomal membrane damage. This unexpected finding reveals that autophagy may play dual, context-dependent roles in proteostasis, acting not only as a protective mechanism but also, under certain conditions, as a contributor to cellular stress.
    Keywords:  Aging; autophagy; protein aggregates; proteostasis; rejuvenation; stress
    DOI:  https://doi.org/10.1080/15548627.2025.2541430
  10. Nat Commun. 2025 Oct 20. 16(1): 9257
    Enhanced hybridization-proximity labeling discovers protein interactomes of single RNA molecules.
    Karen Yap, Tek Hong Chung, Erin C Hedges, Agnes L Nishimura, Christopher E Shaw, Eugene V Makeyev.
      RNAs engage diverse protein partners and localize to specific subcellular compartments, yet dissecting proteomes associated with low-abundance or dispersed RNA molecules remains a challenge. We present an enhanced hybridization-proximity labeling (HyPro) technology for in situ proteome profiling of endogenously expressed RNA microcompartments. We re-engineer the HyPro enzyme and optimize proximity biotinylation conditions to identify proteins associated with compact RNA-containing nuclear bodies, small pre-mRNA clusters, and individual transcripts. Applying this approach to pathogenic G4C2 repeat-containing C9orf72 RNAs, retained as single-molecule foci in the nuclei of amyotrophic lateral sclerosis (ALS) patient-derived pluripotent stem cells, we reveal extensive interactions with disease-linked paraspeckle markers and a specific set of pre-mRNA splicing factors. These findings highlight early RNA processing and localization defects in ALS that may contribute to this late-onset neurodegenerative disorder. Overall, HyPro provides a broadly applicable platform for mapping RNA-protein interactions, enabling insights into RNA biology and its dysregulation in disease.
    DOI:  https://doi.org/10.1038/s41467-025-64282-5
  11. Nat Neurosci. 2025 Oct 21.
    TDP-43 loss induces cryptic polyadenylation in ALS/FTD.
    NYGC ALS Consortium
      Nuclear depletion and cytoplasmic aggregation of the RNA-binding protein TDP-43 are cellular hallmarks of amyotrophic lateral sclerosis (ALS). TDP-43 nuclear loss causes de-repression of cryptic exons, yet cryptic alternative polyadenylation (APA) events have been largely overlooked. In this study, we developed a bioinformatic pipeline to reliably identify alternative last exons, 3' untranslated region (3'UTR) extensions and intronic polyadenylation APA event types, and we identified cryptic APA sites induced by TDP-43 loss in induced pluripotent stem cell (iPSC)-derived neurons. TDP-43 binding sites are enriched at sites of these cryptic events, and TDP-43 can both repress and enhance APA. All categories of cryptic APA were also identified in ALS and frontotemporal dementia (FTD) postmortem brain tissue. RNA sequencing (RNA-seq), thiol(SH)-linked alkylation for the metabolic sequencing of RNA (SLAM-seq) and ribosome profiling (Ribo-seq) revealed that distinct cryptic APA categories have different downstream effects on transcript levels and that cryptic 3'UTR extensions can increase RNA stability, leading to increased translation. In summary, we demonstrate that TDP-43 nuclear depletion induces cryptic APA, expanding the palette of known consequences of TDP-43.
    DOI:  https://doi.org/10.1038/s41593-025-02050-w
  12. FEBS Lett. 2025 Oct 22.
    Quantifying subpercent nuclear TDP-43 loss in cells and ALS cortex using junction-specific cryptic exon RT-qPCR.
    Shingo Koide, Ichiko Ikegami, Ryutaro Hanyu, Yuka Mitsuhashi Koike, Takuma Yamagishi, Genri Toyama, Aya Washida, Mari Tada, Akiyoshi Kakita, Osamu Onodera, Akihiro Sugai.
      Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive neurodegenerative diseases characterised by nuclear TDP-43 loss. Its hallmark, cryptic exon (CE) splicing, is often masked in bulk tissue analyses by the low abundance of affected neurons. We developed an ultrasensitive RT-qPCR assay targeting STMN2 CE using one exon-CE junction-spanning primer and the other within the CE. The design expands the dynamic range sevenfold: TDP-43 knockdown boosted STMN2 CE levels 1395-fold in differentiated SH-SY5Y neurons. Spike-in tests set detection at 0.16% deficient cells. Crucially, the assay revealed a 42-fold CE increase in ALS motor cortex, previously missed by conventional primers. This streamlined tool enables precise quantification of TDP-43 dysfunction and sensitive pharmacodynamic monitoring for future ALS-FTD therapeutic studies. Impact statement Because cryptic-exon signals are diluted in bulk tissue, we developed a junction-spanning STMN2 RT-qPCR with sub-percent sensitivity. This deployable biomarker will aid ALS/FTD researchers and drug developers by standardizing measurements and enabling sensitive pharmacodynamic monitoring of therapies targeting nuclear TDP-43 dysfunction.
    Keywords:  STMN2 biomarker; TDP‐43 proteinopathy; amyotrophic lateral sclerosis; cryptic exon; junction‐specific RT‐qPCR
    DOI:  https://doi.org/10.1002/1873-3468.70198
  13. Dev Cell. 2025 Oct 20. pii: S1534-5807(25)00570-2. [Epub ahead of print]60(20): 2701-2702
    ATG9 assists lipid replenishment for lysosome membrane repair.
    Hemmo Meyer, Bojana Kravic.
      Lysosomal membranes can be permeabilized under various conditions with detrimental consequences for the cell. In this issue, de Tito et al. report that the lipid scramblase ATG9, best known for its role in autophagosome formation, helps distribute lipids from the ER to reseal the limiting membrane and restore lysosomal function.
    DOI:  https://doi.org/10.1016/j.devcel.2025.09.010
  14. Cell Death Dis. 2025 Oct 21. 16(1): 747
    Mitochondrial calcium overload is the trigger for carbon monoxide neurotoxicity.
    Plamena R Angelova, Artyom Y Baev, Sergey O Bachurin, Isabella Myers, Andrey Y Abramov.
      Carbon monoxide is an important gasotransmitter and regulator of cell function in different tissues, including the central nervous system. However, in large doses, it is a poisonous gas that causes mortality and morbidity. Moreover, the majority of survivors of high-dose exposures develop serious neurological conditions. Here, we studied the effect of toxic concentrations of carbon monoxide released from the compound CORM-401 and its removal (re-oxygenation) on calcium signalling in primary cortical neurons and astrocytes. We found that CO induces changes in intracellular Ca2+ concentration in both neurons and astrocytes. The mechanism of these signals was different-in neurons, it was activated by NMDA and AMPA receptors, while in astrocytes, CO-induced fusion of VNUT2-positive vesicles followed by activation of P2Y receptors. Calcium signal in neurons and astrocytes promotes mitochondrial calcium uptake, which dramatically increases after the removal of CO from the medium, which, in combination with higher rates of production of ROS, induces mitochondrial permeability transition and cell death. CO-induced death of neurons and astrocytes could be prevented with partial inhibition of mitochondrial calcium uptake by Tg2112x and/or inhibition of ROS production in the phase of re-oxygenation. Thus, the bidirectional interaction between mitochondrial calcium overload and production of reactive oxygen species is crucial for CO-induced death of neurons and astrocytes.
    DOI:  https://doi.org/10.1038/s41419-025-08012-1
  15. Curr Cardiol Rep. 2025 Oct 23. 27(1): 145
    Human iPSC-Based in Vitro Cardiovascular Tissue Models for Drug Screening Applications.
    Shivesh Anand, Gaoxian Chen, Astha Khanna, Ngan F Huang.
       PURPOSE OF REVIEW: To provide an overview of human induced pluripotent stem cell (hiPSC)-derived cardiovascular lineages and describe their impact on drug testing in vitro.
    RECENT FINDINGS: hiPSCs have garnered tremendous interest over the last decade due to their potential for unlimited proliferation and differentiation into cardiovascular lineages. Technologies using tissue engineering, 3D bioprinting, and organ-on-a-chip platforms composed of hiPSC derivatives can produce cardiovascular tissue mimetics that enhance drug screening applications. hiPSC-derived cardiovascular lineages advance drug screening efforts by using autologous cells that are more therapeutically relevant. Established approaches to reproducibly generate hiPSC-derived cardiovascular lineages and their subsequent organization into 3D constructs more accurately mimic the physiological organization of cardiac tissue, leading to improved identification of potential drug targets for therapeutic testing.
    Keywords:  Cardiovascular; Drug screening; Induced pluripotent stem cell; Organ-on-a-chip; Tissue engineering
    DOI:  https://doi.org/10.1007/s11886-025-02284-x
  16. J Biol Chem. 2025 Oct 22. pii: S0021-9258(25)02705-X. [Epub ahead of print] 110853
    Development of a robust, physiologically relevant neuronal tau aggregation assay for tau-related drug discovery.
    Jessica W Wu, Katherine Titterton, Rebecca Sebastian, Nandini Romanul, Kiran Yanamandra, Bryan Mastis, Rui Chang, Saurabh Khasnavis, Taekyung Kwon, Yating Chai, Justine D Manos, Christina N Preiss, Miwei Hu, Alessandra M Welker, Fan Liao, Tammy Dellovade, Eric Karran, Xavier Langlois.
      Therapeutic interventions to block extracellular tau seeding to prevent endogenous tau aggregation and progression of Alzheimer's disease pathology are currently being investigated in clinical trials. However, the translation of promising preclinical findings to benefit clinical outcomes remains problematic due to the lack of pathophysiological models that recapitulate key features of sporadic Alzheimer's disease-related tauopathies. We developed a primary neuronal tau (hTau) seeding and propagation model. Neurons expressing wild-type human tau protein at a physiological level, seeded with a sub-nanomolar tau derived from Alzheimer's disease brain tissues, rapidly and robustly form tau aggregates and develop impaired mitochondria function. Resulting aggregates are quantitatively measured using automated high content algorithms. The considerable pathophysiological relevance coupled with a highly sensitive dynamic range makes this assay a valuable model system for studying tau pathobiology and an efficient screening tool for modulators of tau aggregation. Using this model, we demonstrate that by targeting a phosphorylation specific epitope of tau, an antibody effectively stops tau aggregation.
    Keywords:  Alzheimer’s disease; Tau aggregation; antibody; hTau neurons; tau propagation
    DOI:  https://doi.org/10.1016/j.jbc.2025.110853
  17. J Cell Biol. 2026 Jan 05. pii: e202501145. [Epub ahead of print]225(1):
    TMEM175 does not function as a proton-selective ion channel to prevent lysosomal over-acidification.
    Erika Riederer, Vedrana Mikusevic, Tuoxian Tang, Lillian Martin, Joseph A Mindell, Dejian Ren.
      The acidic pH of lysosomes required for function is established by the electrogenic V-ATPase proton pump. How lysosomes prevent hyper-acidification by the pump is not well established. Recently, the Parkinson's disease (PD)-associated protein TMEM175 was proposed as a H+-selective channel to leak protons to counter over-acidification. We rigorously address key findings and predictions of this model and show that, in the lysosome, TMEM175 predominantly conducts K+ and is not a H+-selective channel. The native lysosomal H+ leak is remarkably small, ∼0.02 fA, strongly arguing against major contributions from an ion channel. The predominant effect of TMEM175 deficiencies is lysosomal alkalinization in challenged cells, which is further evidence arguing against TMEM175 as a H+-selective channel and can be explained by K+ conductance through TMEM175. Also, lysosomes can be hyper-acidified by manipulations in the presence or absence of TMEM175. Our studies clarify a basic lysosomal biological problem and provide insights into the working mechanism of TMEM175 and its contribution to PD pathology.
    DOI:  https://doi.org/10.1083/jcb.202501145
  18. Alzheimers Dement. 2025 Oct;21(10): e70789
    Beyond prion-like spreading in neurodegenerative disease.
    Georg Meisl, James B Rowe, David Klenerman.
      To design effective therapies for neurodegenerative diseases, it is critical to understand the processes that trigger protein aggregation in sequential brain regions as the disease progresses. Aggregates formed in many neurodegenerative diseases, including Alzheimer's and Parkinson's disease, are capable of seeding, leading to the proposal to regard them all as prion-like. We here argue that the utility of this classification is limited; the terms protein misfolding and aggregation-related diseases describe the general class of diseases, and the connotation of prion-like that the spreading of infectious prions is the rate-limiting process narrows the view of possible mechanisms. Instead, we suggest four factors along which to compare different diseases and model systems, providing a clearer basis to consider the different ways in which pathology can spread, account for factors beyond the aggregating protein, such as declining protein homeostasis with age, and understand the differences between model systems and human disease. HIGHLIGHTS: Four aspects by which to classify neurodegenerative diseases are proposed. Aggregates in health and inflammation are important factors. Prion-like spreading classification is not sufficient to capture the necessary nuance. Different diseases and model systems are dominated by different aspects.
    Keywords:  aggregate removal; disease mechanisms; neurodegeneration; prion‐like; protein aggregation; protein homeostasis
    DOI:  https://doi.org/10.1002/alz.70789
  19. Curr Opin Cell Biol. 2025 Oct 16. pii: S0955-0674(25)00131-0. [Epub ahead of print]97 102593
    Actin cytoskeleton protection by the formin-mediated safety valve.
    Fernando R Valencia, Sergey V Plotnikov.
      Mechanical forces shape cellular form and function by regulating key cellular processes; however, when dysregulated, they contribute to disease. Excessive forces can be detrimental to cells, damaging cytoskeleton, deforming nuclei, and even rupturing the cell itself. To counteract these effects, cells deploy protective mechanisms that enhance mechanical resilience. Emerging evidence highlights a novel strategy for rapid tension release via force-dependent actin polymerization mediated by formin-family proteins such as Dia1. Acting as a mechanical "safety valve", Dia1 buffers otherwise damaging stress and promotes zyxin-mediated repair, preserving cytoskeletal architecture, safeguarding the nucleus, and maintaining cellular integrity. Loss of Dia1 disrupts signaling cascades that converge on key mechanotransduction processes governing cell fate and disease progression. In this review, we explore recent advances in force-dependent actin polymerization and its role in cytoskeletal protection, nuclear homeostasis, and cellular adaptation to mechanical forces.
    DOI:  https://doi.org/10.1016/j.ceb.2025.102593
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