bims-axbals Biomed News
on Axonal biology and ALS
Issue of 2025–03–23
ten papers selected by
TJ Krzystek
  1. A molecular systems architecture of neuromuscular junction in amyotrophic lateral sclerosis.
  2. TBCK-deficiency leads to compartment-specific mRNA and lysosomal trafficking defects in patient-derived neurons.
  3. Extracellular chaperones in lysosomal storage diseases.
  4. Mitochondria-Lysosome Contact Sites: Emerging Players in Cellular Homeostasis and Disease.
  5. Exploring human brain development and disease using assembloids.
  6. MAPT mutations in amyotrophic lateral sclerosis: clinical, neuropathological and functional insights.
  7. Transcriptomic analysis of intracellular RNA granules and small extracellular vesicles: Unmasking their overlap in a cell model of Huntington's disease.
  8. Advances in mitophagy initiation mechanisms.
  9. Mitochondrial fission - changing perspectives for future progress.
  10. Ca2+-triggered (de)ubiquitination events in synapses.
  1. NPJ Syst Biol Appl. 2025 Mar 17. 11(1): 27
    A molecular systems architecture of neuromuscular junction in amyotrophic lateral sclerosis.
    V A Shiva Ayyadurai, Prabhakar Deonikar, Roger D Kamm.
      A molecular systems architecture is presented for the neuromuscular junction (NMJ) in order to provide a framework for organizing complexity of biomolecular interactions in amyotrophic lateral sclerosis (ALS) using a systematic literature review process. ALS is a fatal motor neuron disease characterized by progressive degeneration of the upper and lower motor neurons that supply voluntary muscles. The neuromuscular junction contains cells such as upper and lower motor neurons, skeletal muscle cells, astrocytes, microglia, Schwann cells, and endothelial cells, which are implicated in pathogenesis of ALS. This molecular systems architecture provides a multi-layered understanding of the intra- and inter-cellular interactions in the ALS neuromuscular junction microenvironment, and may be utilized for target identification, discovery of single and combination therapeutics, and clinical strategies to treat ALS.
    DOI:  https://doi.org/10.1038/s41540-025-00501-5
  2. bioRxiv. 2025 Mar 07. pii: 2025.03.02.641041. [Epub ahead of print]
    TBCK-deficiency leads to compartment-specific mRNA and lysosomal trafficking defects in patient-derived neurons.
    Marco Flores-Mendez, Jesus A Tintos-Hernández, Leonardo Ramos-Rodriguez, Leann Miles, Tsz Y Lo, Yuanquan Song, Xilma R Ortiz-González.
      Monogenic pediatric neurodegenerative disorders can reveal fundamental cellular mechanisms that underlie selective neuronal vulnerability. TBCK-Encephaloneuronopathy (TBCKE) is a rare autosomal recessive disorder caused by stop-gain variants in the TBCK gene. Clinically, patients show evidence of profound neurodevelopmental delays, but also symptoms of progressive encephalopathy and motor neuron disease. Yet, the physiological role of TBCK protein remains unclear. We report a human neuronal TBCKE model, derived from iPSCs homozygous for the Boricua variant (p.R126X). Using unbiased proteomic analyses of human neurons, we find TBCK interacts with PPP1R21, C12orf4, and Cryzl1, consistent with TBCK being part of the FERRY mRNA transport complex. Loss of TBCK leads to depletion of C12ORF4 protein levels across multiple cell types, suggesting TBCK may also play a role regulating at least some members of the FERRY complex. We find that TBCK preferentially, but not exclusively, localizes to the surface of endolysosomal vesicles and can colocalize with mRNA in lysosomes. Furthermore, TBCK-deficient neurons have reduced mRNA content in the axonal compartment relative to the soma. TBCK-deficient neurons show reduced levels of the lysosomal dynein/dynactin adapter protein JIP4, which functionally leads to TBCK-deficient neurons exhibiting striking lysosomal axonal retrograde trafficking defects. Hence, our work reveals that TBCK can mediate endolysosomal trafficking of mRNA, particularly along lysosomes in human axonal compartments. TBCK-deficiency leads to compartment-specific mRNA and lysosomal trafficking defects in neurons, which likely contribute to the preferential susceptibility to neurodegeneration.
    DOI:  https://doi.org/10.1101/2025.03.02.641041
  3. Mol Genet Metab. 2025 Mar 15. pii: S1096-7192(25)00077-0. [Epub ahead of print]145(1): 109086
    Extracellular chaperones in lysosomal storage diseases.
    Aslı İnci, Serap Dökmeci.
      Lysosomal storage disorders (LSDs) are a diverse group of inherited metabolic disorders characterized by the accumulation of undegraded substrates within lysosomes due to defective lysosomal function. Recent research has highlighted the pivotal role of extracellular chaperones in the pathophysiology of LSDs, revealing their crucial involvement in modulating disease progression. These chaperones aid in stabilizing and refolding misfolded lysosomal enzymes, enhancing their proper trafficking and function, which in turn reduces substrate accumulation. Furthermore, extracellular chaperones have emerged as promising biomarkers, with their levels in bodily fluids offering potential for disease diagnosis and monitoring. This review explores the current understanding of extracellular chaperones in the context of LSDs, examining their mechanisms of action, biomarker and therapeutic potential, and future directions in clinical application of LSDs.
    Keywords:  Biomarker; Chaperones; Extracellular chaperones; Lysosomal storage disorders; Therapeutic intervention
    DOI:  https://doi.org/10.1016/j.ymgme.2025.109086
  4. Contact (Thousand Oaks). 2025 Jan-Dec;8:8 25152564251329250
    Mitochondria-Lysosome Contact Sites: Emerging Players in Cellular Homeostasis and Disease.
    Francesca Rizzollo, Patrizia Agostinis.
      Mitochondria and lysosomes regulate a multitude of biological processes that are essential for the maintenance of nutrient and metabolic homeostasis and overall cell viability. Recent evidence reveals that these pivotal organelles, similarly to others previously studied, communicate through specialized membrane contact sites (MCSs), hereafter referred to as mitochondria-lysosome contacts (or MLCs), which promote their dynamic interaction without involving membrane fusion. Signal integration through MLCs is implicated in key processes, including mitochondrial fission and dynamics, and the exchange of calcium, cholesterol, and amino acids. Impairments in the formation and function of MLCs are increasingly associated with age-related diseases, specifically neurodegenerative disorders and lysosomal storage diseases. However, MLCs may play roles in other pathological contexts where lysosomes and mitochondria are crucial. In this review, we introduce the methodologies used to study MLCs and discuss known molecular players and key factors involved in their regulation in mammalian cells. We also argue other potential regulatory mechanisms depending on the acidic lysosomal pH and their impact on MLC's function. Finally, we explore the emerging implications of dysfunctional mitochondria-lysosome interactions in disease, highlighting their potential as therapeutic targets in cancer.
    Keywords:  lysosome; membrane contact sites; mitochondria; mitochondria-lysosome contacts
    DOI:  https://doi.org/10.1177/25152564251329250
  5. Neuron. 2025 Mar 11. pii: S0896-6273(25)00128-X. [Epub ahead of print]
    Exploring human brain development and disease using assembloids.
    Sih-Rong Wu, Tomasz J Nowakowski.
      How the human brain develops and what goes awry in neurological disorders represent two long-lasting questions in neuroscience. Owing to the limited access to primary human brain tissue, insights into these questions have been largely gained through animal models. However, there are fundamental differences between developing mouse and human brain, and neural organoids derived from human pluripotent stem cells (hPSCs) have recently emerged as a robust experimental system that mimics self-organizing and multicellular features of early human brain development. Controlled integration of multiple organoids into assembloids has begun to unravel principles of cell-cell interactions. Moreover, patient-derived or genetically engineered hPSCs provide opportunities to investigate phenotypic correlates of neurodevelopmental disorders and to develop therapeutic hypotheses. Here, we outline the advances in technologies that facilitate studies by using assembloids and summarize their applications in brain development and disease modeling. Lastly, we discuss the major roadblocks of the current system and potential solutions.
    Keywords:  assembloid; cell-cell interaction; co-culture; neurodevelopment; neurological disorder; organoid
    DOI:  https://doi.org/10.1016/j.neuron.2025.02.010
  6. J Neurol. 2025 Mar 18. 272(4): 272
    MAPT mutations in amyotrophic lateral sclerosis: clinical, neuropathological and functional insights.
    Sibylle De Bertier, Géraldine Lautrette, Maria-Del-Mar Amador, Tomoko Miki, Séverine Boillée, Christian Stefan Lobsiger, Delphine Bohl, Frederic Darios, Selma Machat, Mathilde Duchesne, Patrick Vourc'h, Anne-Laure Fauret-Amsellem, Philippe Corcia, Nathalie Guy, Philippe Couratier, Danielle Seilhean, Stéphanie Millecamps.
       BACKGROUND: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are part of a well-established disease continuum, underpinned by TDP43-pathology. In contrast, the clinical manifestations of Tau-linked disorders are typically limited to cognitive phenotypes or atypical parkinsonism, although few reports describe motor neuron involvement associated with MAPT (microtubule-associated protein Tau) mutations. This study aimed to investigate the contribution of MAPT to the ALS phenotype.
    METHODS: We analyzed a whole-exome sequencing database comprising 470 ALS patients and explored the pathogenicity of the identified variants through familial, clinical, neuropathological, and cellular studies.
    RESULTS: We identified two missense variants in the Tau repeat domains: the novel p.I308T variant, in a patient with early-onset ALS, and the p.P364S mutation in three families with spinal- or respiratory-onset ALS. Segregation of this mutation with disease could be confirmed in two affected cousins. The observation of p.P364S patient's tissue showed accumulations of hyperphosphorylated Tau in various brain regions, prominent in the motor cortex with Lewy body-like inclusions, along with a C-terminal cleaved form of Tau in muscle. In NSC-34 motor neuron cells expressing p.I308T or p.P364S mutants, Tau was discontinuous along the neurites, with clusters of mitochondria resulting from impaired mitochondrial motility.
    CONCLUSION: These findings expand the molecular understanding of ALS to include MAPT mutations. MAPT analysis should be incorporated into ALS genetic screening, particularly in patients with a familial history of the disease. Recognizing the full spectrum of MAPT-linked neurodegenerative diseases is of considerable interest, given the ongoing efforts to develop MAPT-targeted therapies.
    Keywords:  ALS; Genetics; MAPT; Motor neuron disease; Mutation; TAU; Tauopathies
    DOI:  https://doi.org/10.1007/s00415-025-13007-1
  7. Mol Cell Probes. 2025 Mar 14. pii: S0890-8508(25)00019-2. [Epub ahead of print]81 102026
    Transcriptomic analysis of intracellular RNA granules and small extracellular vesicles: Unmasking their overlap in a cell model of Huntington's disease.
    Deepti Kailash Nabariya, Lisa Maria Knüpfer, Patrick Hartwich, Manuela S Killian, Florian Centler, Sybille Krauß.
      Huntington's disease (HD) arises from the abnormal expansion of a CAG repeat in the HTT gene. The mutant CAG repeat triggers aberrant RNA-protein interactions and translates into toxic aggregate-prone polyglutamine protein. These aberrant RNA-protein ineractions also seed the formation of cytoplasmic liquid-like granules, such as stress granules. Emerging evidence demonstrates that granules formed via liquid-liquid phase separation can mature into gel-like inclusions that persist within the cell and may act as precursor to aggregates that occur in patients' tissue. Thus, deregulation of RNA granules is an important component of neurodegeneration. Interestingly, both the formation of intracellular membrane-less organelles like stress granules and the secretion of small extracellular vesicles (sEVs) increase upon stress and under disease conditions. sEVs are lipid membrane-bound particles that are secreted from all cell types and may participate in the spreading of misfolded proteins and aberrant RNA-protein complexes across the central nervous system in neurodegenerative diseases like HD. In this study, we performed a comparative transcriptomic analysis of sEVs and RNA granules in an HD model. RNA granules and sEVs were isolated from an inducible HD cell model. Both sEVs and RNA granules were isolated from induced (HD) and non-induced (control) cells and analyzed by RNA sequencing. Our comparative analysis between the transcriptomics data of HD RNA granules and sEVs showed that: (I) intracellular RNA granules and extracellular RNA vesicles share content, (II) several non-coding RNAs translocate to RNA granules, and (III) the composition of RNA granules and sEVs is affected in HD cells. Our data showing common transcripts in intracellular RNA granules and extracellular sEVs suggest that formation of RNA granules and sEV loading may be related. Moreover, we found a high abundance of lncRNAs in both control and HD samples, with several transcripts under REST regulation, highlighting their potential role in HD pathogenesis and selective incorporation into sEVs. The transcriptome cargo of RNA granules or sEVs may serve as a source for diagnostic strategies. For example, disease-specific RNA-signatures of sEVs can serve as biomarker of central nervous system diseases. Therefore, we compared our dataset to transcriptomic data from HD patient sEVs in blood. However, our data suggest that the cell-type specific signature of sEV-secreted RNAs as well as their high variability may make it difficult to detect these biomarkers in blood.
    Keywords:  Extracellular vesicles; Huntington's disease; Neurodegeneration; RNA binding proteins; RNA granules; Stress granules
    DOI:  https://doi.org/10.1016/j.mcp.2025.102026
  8. Curr Opin Cell Biol. 2025 Mar 20. pii: S0955-0674(25)00031-6. [Epub ahead of print]94 102493
    Advances in mitophagy initiation mechanisms.
    Catharina Küng, Michael Lazarou, Thanh Ngoc Nguyen.
      Mitophagy is an important lysosomal degradative pathway that removes damaged or unwanted mitochondria to maintain cellular and organismal homeostasis. The mechanisms behind how mitophagy is initiated to form autophagosomes around mitochondria have gained a lot of interest since they can be potentially targeted by mitophagy-inducing therapeutics. Mitophagy initiation can be driven by various autophagy receptors or adaptors that respond to different cellular and mitochondrial stimuli, ranging from mitochondrial damage to metabolic rewiring. This review will cover recent advances in our understanding of how mitophagy is initiated, and by doing so reveal the mechanistic plasticity of how autophagosome formation can begin.
    DOI:  https://doi.org/10.1016/j.ceb.2025.102493
  9. J Cell Sci. 2025 May 01. pii: jcs263640. [Epub ahead of print]138(9):
    Mitochondrial fission - changing perspectives for future progress.
    Sukrut C Kamerkar, Ao Liu, Henry N Higgs.
      Mitochondrial fission is important for many aspects of cellular homeostasis, including mitochondrial distribution, stress response, mitophagy, mitochondrially derived vesicle production and metabolic regulation. Several decades of research has revealed much about fission, including identification of a key division protein - the dynamin Drp1 (also known as DNM1L) - receptors for Drp1 on the outer mitochondrial membrane (OMM), including Mff, MiD49 and MiD51 (also known as MIEF2 and MIEF1, respectively) and Fis1, and important Drp1 regulators, including post-translational modifications, actin filaments and the phospholipid cardiolipin. In addition, it is now appreciated that other organelles, including the endoplasmic reticulum, lysosomes and Golgi-derived vesicles, can participate in mitochondrial fission. However, a more holistic understanding of the process is lacking. In this Review, we address three questions that highlight knowledge gaps. First, how do we quantify mitochondrial fission? Second, how does the inner mitochondrial membrane (IMM) divide? Third, how many 'types' of fission exist? We also introduce a model that integrates multiple regulatory factors in mammalian mitochondrial fission. In this model, three possible pathways (cellular stimulation, metabolic switching or mitochondrial dysfunction) independently initiate Drp1 recruitment at the fission site, followed by a shared second step in which Mff mediates subsequent assembly of a contractile Drp1 ring. We conclude by discussing some perplexing issues in fission regulation, including the effects of Drp1 phosphorylation and the multiple Drp1 isoforms.
    Keywords:  Drp1 receptors; Dynamin related protein-1; Inner mitochondrial membrane division; Mitochondrial fission
    DOI:  https://doi.org/10.1242/jcs.263640
  10. Mol Cell Proteomics. 2025 Mar 13. pii: S1535-9476(25)00044-1. [Epub ahead of print] 100946
    Ca2+-triggered (de)ubiquitination events in synapses.
    Sofia Ainatzi, Svenja V Kaufmann, Ivan Silbern, Svilen V Georgiev, Sonja Lorenz, Silvio O Rizzoli, Henning Urlaub.
      Neuronal communication relies on neurotransmitter release from synaptic vesicles (SVs), whose dynamics are controlled by Ca2+-dependent pathways, as many thoroughly studied phosphorylation cascades. However, little is known about other post-translational modifications, as ubiquitination. To address this, we analysed resting and stimulated synaptosomes (isolated synapses) by quantitative mass spectrometry. We identified more than 5,000 ubiquitination sites on ∼2,000 proteins, the majority of which participate in SV recycling processes. Several proteins showed significant changes in ubiquitination in response to Ca2+ influx, with the most pronounced changes in CaMKIIα and the clathrin adaptor protein AP180. To validate this finding, we generated a CaMKIIα mutant lacking the ubiquitination target site (K291) and analysed it both in neurons and non-neuronal cells. K291 ubiquitination, close to an important site for CaMKIIα autophosphorylation (T286), influences the synaptic function of this kinase. We suggest that ubiquitination in response to synaptic activity is an important regulator of synaptic function.
    DOI:  https://doi.org/10.1016/j.mcpro.2025.100946
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