23 results on '"Tantardini, Elena'
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2. Loss of TDP‐43 oligomerization or RNA binding elicits distinct aggregation patterns
- Author
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Pérez‐Berlanga, Manuela, Wiersma, Vera I, Zbinden, Aurélie, De Vos, Laura, Wagner, Ulrich, Foglieni, Chiara, Mallona, Izaskun, Betz, Katharina M, Cléry, Antoine, Weber, Julien, Guo, Zhongning, Rigort, Ruben, de Rossi, Pierre, Manglunia, Ruchi, Tantardini, Elena, Sahadevan, Sonu, Stach, Oliver, Hruska‐Plochan, Marian, Allain, Frederic H‐T, Paganetti, Paolo, and Polymenidou, Magdalini
- Published
- 2023
- Full Text
- View/download PDF
3. LAG3 is not expressed in human and murine neurons and does not modulate α‐synucleinopathies
- Author
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Marc Emmenegger, Elena De Cecco, Marian Hruska‐Plochan, Timo Eninger, Matthias M Schneider, Melanie Barth, Elena Tantardini, Pierre de Rossi, Mehtap Bacioglu, Rebekah G Langston, Alice Kaganovich, Nora Bengoa‐Vergniory, Andrès Gonzalez‐Guerra, Merve Avar, Daniel Heinzer, Regina Reimann, Lisa M Häsler, Therese W Herling, Naunehal S Matharu, Natalie Landeck, Kelvin Luk, Ronald Melki, Philipp J Kahle, Simone Hornemann, Tuomas P J Knowles, Mark R Cookson, Magdalini Polymenidou, Mathias Jucker, and Adriano Aguzzi
- Subjects
LAG3 ,neurodegeneration ,prionoids ,α‐synuclein ,Medicine (General) ,R5-920 ,Genetics ,QH426-470 - Abstract
Abstract While the initial pathology of Parkinson’s disease and other α‐synucleinopathies is often confined to circumscribed brain regions, it can spread and progressively affect adjacent and distant brain locales. This process may be controlled by cellular receptors of α‐synuclein fibrils, one of which was proposed to be the LAG3 immune checkpoint molecule. Here, we analysed the expression pattern of LAG3 in human and mouse brains. Using a variety of methods and model systems, we found no evidence for LAG3 expression by neurons. While we confirmed that LAG3 interacts with α‐synuclein fibrils, the specificity of this interaction appears limited. Moreover, overexpression of LAG3 in cultured human neural cells did not cause any worsening of α‐synuclein pathology ex vivo. The overall survival of A53T α‐synuclein transgenic mice was unaffected by LAG3 depletion, and the seeded induction of α‐synuclein lesions in hippocampal slice cultures was unaffected by LAG3 knockout. These data suggest that the proposed role of LAG3 in the spreading of α‐synucleinopathies is not universally valid.
- Published
- 2021
- Full Text
- View/download PDF
4. Synaptic FUS accumulation triggers early misregulation of synaptic RNAs in a mouse model of ALS
- Author
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Sonu Sahadevan, Katharina M. Hembach, Elena Tantardini, Manuela Pérez-Berlanga, Marian Hruska-Plochan, Salim Megat, Julien Weber, Petra Schwarz, Luc Dupuis, Mark D. Robinson, Pierre De Rossi, and Magdalini Polymenidou
- Subjects
Science - Abstract
Mutations in the RNA-binding protein FUS contribute to ALS. Here the authors use CLIP-seq on synaptoneurosomes to identify proteins associated with synapse organization and plasticity that are differentially regulated in a knock-in ALS mouse model.
- Published
- 2021
- Full Text
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5. A model of human neural networks reveals NPTX2 pathology in ALS and FTLD
- Author
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Hruska-Plochan, Marian; https://orcid.org/0000-0002-9253-4362, Wiersma, Vera I; https://orcid.org/0000-0001-8223-4588, Betz, Katharina M; https://orcid.org/0000-0001-5041-6205, Mallona, Izaskun; https://orcid.org/0000-0002-2853-7526, Ronchi, Silvia, Maniecka, Zuzanna, Hock, Eva-Maria, Tantardini, Elena; https://orcid.org/0000-0001-9189-3390, Laferriere, Florent; https://orcid.org/0000-0002-0753-5505, Sahadevan, Sonu, Hoop, Vanessa, Delvendahl, Igor; https://orcid.org/0000-0002-6151-2363, Pérez-Berlanga, Manuela; https://orcid.org/0000-0001-9064-9724, Gatta, Beatrice, Panatta, Martina, van der Bourg, Alexander, Bohaciakova, Dasa; https://orcid.org/0000-0002-9538-6668, Sharma, Puneet; https://orcid.org/0000-0003-0566-9005, De Vos, Laura; https://orcid.org/0000-0001-6675-6968, Frontzek, Karl; https://orcid.org/0000-0002-0945-8857, Aguzzi, Adriano; https://orcid.org/0000-0002-0344-6708, Lashley, Tammaryn; https://orcid.org/0000-0001-7389-0348, Robinson, Mark D, Karayannis, Theofanis; https://orcid.org/0000-0002-3267-6254, Mueller, Martin; https://orcid.org/0000-0003-1624-6761, Hierlemann, Andreas; https://orcid.org/0000-0002-3838-2468, Polymenidou, Magdalini; https://orcid.org/0000-0003-1271-9445, Hruska-Plochan, Marian; https://orcid.org/0000-0002-9253-4362, Wiersma, Vera I; https://orcid.org/0000-0001-8223-4588, Betz, Katharina M; https://orcid.org/0000-0001-5041-6205, Mallona, Izaskun; https://orcid.org/0000-0002-2853-7526, Ronchi, Silvia, Maniecka, Zuzanna, Hock, Eva-Maria, Tantardini, Elena; https://orcid.org/0000-0001-9189-3390, Laferriere, Florent; https://orcid.org/0000-0002-0753-5505, Sahadevan, Sonu, Hoop, Vanessa, Delvendahl, Igor; https://orcid.org/0000-0002-6151-2363, Pérez-Berlanga, Manuela; https://orcid.org/0000-0001-9064-9724, Gatta, Beatrice, Panatta, Martina, van der Bourg, Alexander, Bohaciakova, Dasa; https://orcid.org/0000-0002-9538-6668, Sharma, Puneet; https://orcid.org/0000-0003-0566-9005, De Vos, Laura; https://orcid.org/0000-0001-6675-6968, Frontzek, Karl; https://orcid.org/0000-0002-0945-8857, Aguzzi, Adriano; https://orcid.org/0000-0002-0344-6708, Lashley, Tammaryn; https://orcid.org/0000-0001-7389-0348, Robinson, Mark D, Karayannis, Theofanis; https://orcid.org/0000-0002-3267-6254, Mueller, Martin; https://orcid.org/0000-0003-1624-6761, Hierlemann, Andreas; https://orcid.org/0000-0002-3838-2468, and Polymenidou, Magdalini; https://orcid.org/0000-0003-1271-9445
- Abstract
Human cellular models of neurodegeneration require reproducibility and longevity, which is necessary for simulating age-dependent diseases. Such systems are particularly needed for TDP-43 proteinopathies$^{1}$, which involve human-specific mechanisms$^{2–5}$ that cannot be directly studied in animal models. Here, to explore the emergence and consequences of TDP-43 pathologies, we generated induced pluripotent stem cell-derived, colony morphology neural stem cells (iCoMoNSCs) via manual selection of neural precursors$^{6}$. Single-cell transcriptomics and comparison to independent neural stem cells$^{7}$ showed that iCoMoNSCs are uniquely homogenous and self-renewing. Differentiated iCoMoNSCs formed a self-organized multicellular system consisting of synaptically connected and electrophysiologically active neurons, which matured into long-lived functional networks (which we designate iNets). Neuronal and glial maturation in iNets was similar to that of cortical organoids$^{8}$. Overexpression of wild-type TDP-43 in a minority of neurons within iNets led to progressive fragmentation and aggregation of the protein, resulting in a partial loss of function and neurotoxicity. Single-cell transcriptomics revealed a novel set of misregulated RNA targets in TDP-43-overexpressing neurons and in patients with TDP-43 proteinopathies exhibiting a loss of nuclear TDP-43. The strongest misregulated target encoded the synaptic protein NPTX2, the levels of which are controlled by TDP-43 binding on its 3′ untranslated region. When NPTX2 was overexpressed in iNets, it exhibited neurotoxicity, whereas correcting NPTX2 misregulation partially rescued neurons from TDP-43-induced neurodegeneration. Notably, NPTX2 was consistently misaccumulated in neurons from patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration with TDP-43 pathology. Our work directly links TDP-43 misregulation and NPTX2 accumulation, thereby revealing a TDP-43-dependent pathway of neurotoxic
- Published
- 2024
6. Reactive oxygen species regulate axonal regeneration through the release of exosomal NADPH oxidase 2 complexes into injured axons
- Author
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Hervera, Arnau, De Virgiliis, Francesco, Palmisano, Ilaria, Zhou, Luming, Tantardini, Elena, Kong, Guiping, Hutson, Thomas, Danzi, Matt C., Perry, Rotem Ben-Tov, Santos, Celio X. C., Kapustin, Alexander N., Fleck, Roland A., Del Río, José Antonio, Carroll, Thomas, Lemmon, Vance, Bixby, John L., Shah, Ajay M., Fainzilber, Mike, and Di Giovanni, Simone
- Published
- 2018
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7. Loss of TDP-43 oligomerization or RNA binding elicits distinct aggregation patterns
- Author
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Pérez-Berlanga, Manuela; https://orcid.org/0000-0001-9064-9724, Wiersma, Vera I; https://orcid.org/0000-0001-8223-4588, Zbinden, Aurélie; https://orcid.org/0000-0002-7785-2741, De Vos, Laura; https://orcid.org/0000-0001-6675-6968, Wagner, Ulrich; https://orcid.org/0000-0002-1751-5866, Foglieni, Chiara, Mallona, Izaskun; https://orcid.org/0000-0002-2853-7526, Betz, Katharina M; https://orcid.org/0000-0001-5041-6205, Cléry, Antoine; https://orcid.org/0000-0002-4550-6908, Weber, Julien, Guo, Zhongning, Rigort, Ruben; https://orcid.org/0000-0002-1686-3260, de Rossi, Pierre; https://orcid.org/0000-0002-2356-4269, Manglunia, Ruchi, Tantardini, Elena; https://orcid.org/0000-0001-9189-3390, Sahadevan, Sonu, Stach, Oliver, Hruska-Plochan, Marian; https://orcid.org/0000-0002-9253-4362, Allain, Frederic H-T; https://orcid.org/0000-0002-2131-6237, Paganetti, Paolo; https://orcid.org/0000-0003-1896-6324, Polymenidou, Magdalini; https://orcid.org/0000-0003-1271-9445, Pérez-Berlanga, Manuela; https://orcid.org/0000-0001-9064-9724, Wiersma, Vera I; https://orcid.org/0000-0001-8223-4588, Zbinden, Aurélie; https://orcid.org/0000-0002-7785-2741, De Vos, Laura; https://orcid.org/0000-0001-6675-6968, Wagner, Ulrich; https://orcid.org/0000-0002-1751-5866, Foglieni, Chiara, Mallona, Izaskun; https://orcid.org/0000-0002-2853-7526, Betz, Katharina M; https://orcid.org/0000-0001-5041-6205, Cléry, Antoine; https://orcid.org/0000-0002-4550-6908, Weber, Julien, Guo, Zhongning, Rigort, Ruben; https://orcid.org/0000-0002-1686-3260, de Rossi, Pierre; https://orcid.org/0000-0002-2356-4269, Manglunia, Ruchi, Tantardini, Elena; https://orcid.org/0000-0001-9189-3390, Sahadevan, Sonu, Stach, Oliver, Hruska-Plochan, Marian; https://orcid.org/0000-0002-9253-4362, Allain, Frederic H-T; https://orcid.org/0000-0002-2131-6237, Paganetti, Paolo; https://orcid.org/0000-0003-1896-6324, and Polymenidou, Magdalini; https://orcid.org/0000-0003-1271-9445
- Abstract
Aggregation of the RNA-binding protein TAR DNA-binding protein 43 (TDP-43) is the key neuropathological feature of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). In physiological conditions, TDP-43 is predominantly nuclear, forms oligomers, and is contained in biomolecular condensates assembled by liquid-liquid phase separation (LLPS). In disease, TDP-43 forms cytoplasmic or intranuclear inclusions. How TDP-43 transitions from physiological to pathological states remains poorly understood. Using a variety of cellular systems to express structure-based TDP-43 variants, including human neurons and cell lines with near-physiological expression levels, we show that oligomerization and RNA binding govern TDP-43 stability, splicing functionality, LLPS, and subcellular localization. Importantly, our data reveal that TDP-43 oligomerization is modulated by RNA binding. By mimicking the impaired proteasomal activity observed in ALS/FTLD patients, we found that monomeric TDP-43 forms inclusions in the cytoplasm, whereas its RNA binding-deficient counterpart aggregated in the nucleus. These differentially localized aggregates emerged via distinct pathways: LLPS-driven aggregation in the nucleus and aggresome-dependent inclusion formation in the cytoplasm. Therefore, our work unravels the origins of heterogeneous pathological species reminiscent of those occurring in TDP-43 proteinopathy patients.
- Published
- 2023
8. TDP-43 oligomerization and RNA binding are codependent but their loss elicits distinct pathologies
- Author
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Pérez-Berlanga, Manuela, primary, Wiersma, Vera I., additional, Zbinden, Aurélie, additional, De Vos, Laura, additional, Wagner, Ulrich, additional, Foglieni, Chiara, additional, Mallona, Izaskun, additional, Betz, Katharina M., additional, Cléry, Antoine, additional, Weber, Julien, additional, Guo, Zhongning, additional, Rigort, Ruben, additional, de Rossi, Pierre, additional, Manglunia, Ruchi, additional, Tantardini, Elena, additional, Sahadevan, Sonu, additional, Stach, Oliver, additional, Hruska-Plochan, Marian, additional, Allain, Frederic H.-T., additional, Paganetti, Paolo, additional, and Polymenidou, Magdalini, additional
- Published
- 2022
- Full Text
- View/download PDF
9. LAG3 is not expressed in human and murine neurons and does not modulate α‐synucleinopathies
- Author
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Emmenegger, Marc, De Cecco, Elena, Hruska-Plochan, Marian, Eninger, Timo, Schneider, Matthias M, Barth, Melanie, Tantardini, Elena, De Rossi, Pierre, Bacioglu, Mehtap, Langston, Rebekah G, Kaganovich, Alice, Bengoa-Vergniory, Nora, Gonzalez-Guerra, Andrès, Avar, Merve, Heinzer, Daniel, Reimann, Regina, Häsler, Lisa M, Herling, Therese W, Matharu, Naunehal S, Landeck, Natalie, Luk, Kelvin, Melki, Ronald, Kahle, Philipp J, Hornemann, Simone, Knowles, Tuomas PJ, Cookson, Mark R, Polymenidou, Magdalini, Jucker, Mathias, Aguzzi, Adriano, Universität Zürich [Zürich] = University of Zurich (UZH), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), University of Cambridge [UK] (CAM), National Institutes of Health [Bethesda] (NIH), University of Oxford [Oxford], Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Centre National de la Recherche Scientifique (CNRS)-Service MIRCEN (MIRCEN), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, University of Tübingen, National Centre for Competence in Research (NCCR) RNA & Disease (51NF40-182880), European Project: 670958,H2020,ERC-2014-ADG,PRION2020(2015), European Project: 674979,H2020,H2020-MSCA-ITN-2015,NANOTRANS(2016), European Project: (grant No 116060),IMPRiND, University of Oxford, Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Emmenegger, Marc [0000-0002-6073-8811], De Cecco, Elena [0000-0002-0148-2596], Hruska-Plochan, Marian [0000-0002-9253-4362], Schneider, Matthias M [0000-0002-1894-1859], Tantardini, Elena [0000-0001-9189-3390], Bacioglu, Mehtap [0000-0003-0304-7026], Bengoa-Vergniory, Nora [0000-0002-3700-0464], Avar, Merve [0000-0003-4665-5558], Heinzer, Daniel [0000-0002-3282-4042], Landeck, Natalie [0000-0002-8399-4009], Luk, Kelvin [0000-0002-6591-6269], Melki, Ronald [0000-0003-0000-7096], Hornemann, Simone [0000-0002-2674-9891], Cookson, Mark R [0000-0002-1058-3831], Jucker, Mathias [0000-0001-9045-1072], Aguzzi, Adriano [0000-0002-0344-6708], Apollo - University of Cambridge Repository, Hruska‐Plochan, Marian [0000-0002-9253-4362], Bengoa‐Vergniory, Nora [0000-0002-3700-0464], University of Zurich, and Aguzzi, Adriano
- Subjects
Medicine (General) ,prionoids ,Synucleinopathies ,10208 Institute of Neuropathology ,610 Medicine & health ,Mice, Transgenic ,QH426-470 ,Article ,Mice ,R5-920 ,α-synuclein ,Genetics ,Animals ,Humans ,ddc:610 ,Neurons ,α‐synuclein ,neurodegeneration ,Parkinson Disease ,Articles ,nervous system diseases ,EMBO27 ,1313 Molecular Medicine ,genetics [alpha-Synuclein] ,alpha-Synuclein ,570 Life sciences ,biology ,Molecular Medicine ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,11493 Department of Quantitative Biomedicine ,Neuroscience ,LAG3 - Abstract
Funder: University of Zurich and University Hospital of Zurich, Funder: NOMIS Stiftung (NOMIS Foundation); Id: http://dx.doi.org/10.13039/501100008483, Funder: Forschungskredit University of Zurich, While the initial pathology of Parkinson’s disease and other α‐synucleinopathies is often confined to circumscribed brain regions, it can spread and progressively affect adjacent and distant brain locales. This process may be controlled by cellular receptors of α‐synuclein fibrils, one of which was proposed to be the LAG3 immune checkpoint molecule. Here, we analysed the expression pattern of LAG3 in human and mouse brains. Using a variety of methods and model systems, we found no evidence for LAG3 expression by neurons. While we confirmed that LAG3 interacts with α‐synuclein fibrils, the specificity of this interaction appears limited. Moreover, overexpression of LAG3 in cultured human neural cells did not cause any worsening of α‐synuclein pathology ex vivo. The overall survival of A53T α‐synuclein transgenic mice was unaffected by LAG3 depletion, and the seeded induction of α‐synuclein lesions in hippocampal slice cultures was unaffected by LAG3 knockout. These data suggest that the proposed role of LAG3 in the spreading of α‐synucleinopathies is not universally valid.
- Published
- 2021
- Full Text
- View/download PDF
10. TDP-43 oligomerization and RNA binding are codependent but their loss elicits distinct pathologies
- Author
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Pérez-Berlanga, Manuela; https://orcid.org/0000-0001-9064-9724, Wiersma, Vera; https://orcid.org/0000-0001-8223-4588, Zbinden, Aurélie; https://orcid.org/0000-0002-7785-2741, De Vos, Laura; https://orcid.org/0000-0001-6675-6968, Wagner, Ulrich; https://orcid.org/0000-0002-1751-5866, Foglieni, Chiara, Mallona Gonzalez, Izaskun; https://orcid.org/0000-0002-2853-7526, Betz, Katharina M, Cléry, Antoine; https://orcid.org/0000-0002-4550-6908, Weber, Julien, Guo, Zhongning, Rigort, Ruben, De Rossi, Pierre; https://orcid.org/0000-0002-2356-4269, Manglunia, Ruchi, Tantardini, Elena; https://orcid.org/0000-0001-9189-3390, Sahadevan, Sonu, Stach, Oliver, Hruska-Plochan, Marian; https://orcid.org/0000-0002-9253-4362, Allain, Frederic H-T; https://orcid.org/0000-0002-2131-6237, Paganetti, Paolo; https://orcid.org/0000-0003-1896-6324, Polymenidou, Magdalini; https://orcid.org/0000-0003-1271-9445, Pérez-Berlanga, Manuela; https://orcid.org/0000-0001-9064-9724, Wiersma, Vera; https://orcid.org/0000-0001-8223-4588, Zbinden, Aurélie; https://orcid.org/0000-0002-7785-2741, De Vos, Laura; https://orcid.org/0000-0001-6675-6968, Wagner, Ulrich; https://orcid.org/0000-0002-1751-5866, Foglieni, Chiara, Mallona Gonzalez, Izaskun; https://orcid.org/0000-0002-2853-7526, Betz, Katharina M, Cléry, Antoine; https://orcid.org/0000-0002-4550-6908, Weber, Julien, Guo, Zhongning, Rigort, Ruben, De Rossi, Pierre; https://orcid.org/0000-0002-2356-4269, Manglunia, Ruchi, Tantardini, Elena; https://orcid.org/0000-0001-9189-3390, Sahadevan, Sonu, Stach, Oliver, Hruska-Plochan, Marian; https://orcid.org/0000-0002-9253-4362, Allain, Frederic H-T; https://orcid.org/0000-0002-2131-6237, Paganetti, Paolo; https://orcid.org/0000-0003-1896-6324, and Polymenidou, Magdalini; https://orcid.org/0000-0003-1271-9445
- Abstract
Aggregation of the RNA-binding protein TDP-43 is the main common neuropathological feature of TDP-43 proteinopathies. In physiological conditions, TDP-43 is predominantly nuclear and contained in biomolecular condensates formed via liquid-liquid phase separation (LLPS). However, in disease, TDP-43 is depleted from these compartments and forms cytoplasmic or, sometimes, intranuclear inclusions. How TDP-43 transitions from physiological to pathological states remains poorly understood. Here, we show that self-oligomerization and RNA binding cooperatively govern TDP-43 stability, functionality, LLPS and cellular localization. Importantly, our data reveal that TDP-43 oligomerization is connected to, and conformationally modulated by, RNA binding. Mimicking the impaired proteasomal activity observed in patients, we found that TDP-43 forms nuclear aggregates via LLPS and cytoplasmic aggregates via aggresome formation. The favored aggregation pathway depended on the TDP-43 state –monomeric/oligomeric, RNA-bound/-unbound– and the subcellular environment –nucleus/cytoplasm. Our work unravels the origins of heterogeneous pathological species occurring in TDP-43 proteinopathies.
- Published
- 2022
11. TDP-43 oligomerization and RNA binding are codependent but their loss elicits distinct pathologies
- Author
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Pérez-Berlanga, Manuela, Wiersma, Vera, Zbinden, Aurélie, De Vos, Laura, Wagner, Ulrich, Foglieni, Chiara, Mallona Gonzalez, Izaskun, Betz, Katharina M, Cléry, Antoine, Weber, Julien, Guo, Zhongning, Rigort, Ruben, De Rossi, Pierre, Manglunia, Ruchi, Tantardini, Elena, Sahadevan, Sonu, Stach, Oliver, Hruska-Plochan, Marian, Allain, Frederic H-T, Paganetti, Paolo, Polymenidou, Magdalini, and University of Zurich
- Subjects
610 Medicine & health ,11493 Department of Quantitative Biomedicine - Abstract
Aggregation of the RNA-binding protein TDP-43 is the main common neuropathological feature of TDP-43 proteinopathies. In physiological conditions, TDP-43 is predominantly nuclear and contained in biomolecular condensates formed via liquid-liquid phase separation (LLPS). However, in disease, TDP-43 is depleted from these compartments and forms cytoplasmic or, sometimes, intranuclear inclusions. How TDP-43 transitions from physiological to pathological states remains poorly understood. Here, we show that self-oligomerization and RNA binding cooperatively govern TDP-43 stability, functionality, LLPS and cellular localization. Importantly, our data reveal that TDP-43 oligomerization is connected to, and conformationally modulated by, RNA binding. Mimicking the impaired proteasomal activity observed in patients, we found that TDP-43 forms nuclear aggregates via LLPS and cytoplasmic aggregates via aggresome formation. The favored aggregation pathway depended on the TDP-43 state –monomeric/oligomeric, RNA-bound/-unbound– and the subcellular environment –nucleus/cytoplasm. Our work unravels the origins of heterogeneous pathological species occurring in TDP-43 proteinopathies.
- Published
- 2022
- Full Text
- View/download PDF
12. NOX-dependent reactive oxygen species are essential regulators of axonal regeneration
- Author
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Hervera, Arnau, De Virgiliis, Francesco, Palmisano, Ilaria, Zhou, Luming, Tantardini, Elena, Kong, Guiping, Hutson, Thomas, Danzi, Matt C., Ben-Tov Perry, Rotem, Santos, Celio X.C., Del Río, José Antonio, Carroll, Thomas, Lemmon, Vance, Bixby, John L., Shah, Ajay M., Fainzilber, Mike, and Di Giovanni, Simone
- Published
- 2021
- Full Text
- View/download PDF
13. Publisher Correction: Reactive oxygen species regulate axonal regeneration through the release of exosomal NADPH oxidase 2 complexes into injured axons
- Author
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Hervera, Arnau, De Virgiliis, Francesco, Palmisano, Ilaria, Zhou, Luming, Tantardini, Elena, Kong, Guiping, Hutson, Thomas, Danzi, Matt C., Perry, Rotem Ben-Tov, Santos, Celio X. C., Kapustin, Alexander N., Fleck, Roland A., Del Río, José Antonio, Carroll, Thomas, Lemmon, Vance, Bixby, John L., Shah, Ajay M., Fainzilber, Mike, and Di Giovanni, Simone
- Published
- 2018
- Full Text
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14. Author Reply to Peer Reviews of LAG3 is not expressed in human and murine neurons and does not modulate α-synucleinopathies
- Author
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Adriano Aguzzi, Mathias Jucker, Magdalini Polymenidou, Mark R. Cookson, Tuomas P. J. Knowles, Simone Hornemann, Philipp J. Kahle, Ronald Melki, Kelvin Luk, Natalie Landeck, Naunehal S. Matharu, Therese W. Herling, Lisa M. Häsler, Regina Reimann, Daniel Heinzer, Merve Avar, Andrès Gonzalez-Guerra, Nora Bengoa-Vergniory, Alice Kaganovich, Rebekah G. Langston, Mehtap Bacioglu, Pierre de Rossi, Elena Tantardini, Melanie Barth, Matthias M. Schneider, Timo Eninger, Marian Hruska-Plochan, Elena De Cecco, and Marc Emmenegger
- Published
- 2021
- Full Text
- View/download PDF
15. Synaptic FUS accumulation triggers early misregulation of synaptic RNAs in a mouse model of ALS
- Author
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Pierre De Rossi, Marian Hruska-Plochan, Magdalini Polymenidou, Mark D. Robinson, Elena Tantardini, Luc Dupuis, Salim Megat, Julien Weber, Katharina M. Hembach, Petra Schwarz, Sonu Sahadevan, Manuela Pérez-Berlanga, Universität Zürich [Zürich] = University of Zurich (UZH), Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), University hospital of Zurich [Zurich], Dieterle, Stéphane, University of Zurich, and Polymenidou, Magdalini
- Subjects
0301 basic medicine ,[SDV]Life Sciences [q-bio] ,General Physics and Astronomy ,MESH: Synapses ,Synapse ,Mice ,0302 clinical medicine ,MESH: Animals ,Amyotrophic lateral sclerosis ,MESH: Amyotrophic Lateral Sclerosis ,Cerebral Cortex ,Multidisciplinary ,MESH: RNA-Binding Protein FUS ,Neurodegeneration ,10124 Institute of Molecular Life Sciences ,3100 General Physics and Astronomy ,Cell biology ,[SDV] Life Sciences [q-bio] ,GABAergic ,Microtubule-Associated Proteins ,MESH: Cell Nucleus ,Science ,1600 General Chemistry ,Genetics and Molecular Biology ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,1300 General Biochemistry, Genetics and Molecular Biology ,MESH: Mice, Inbred C57BL ,MESH: RNA ,medicine ,Animals ,RNA, Messenger ,Synapse organization ,MESH: Mice ,MESH: RNA, Messenger ,RNA metabolism ,Cell Nucleus ,Messenger RNA ,Amyotrophic Lateral Sclerosis ,RNA ,General Chemistry ,medicine.disease ,MESH: Cerebral Cortex ,Mice, Inbred C57BL ,MESH: Microtubule-Associated Proteins ,Disease Models, Animal ,030104 developmental biology ,General Biochemistry ,Synapses ,570 Life sciences ,biology ,RNA-Binding Protein FUS ,MESH: Disease Models, Animal ,11493 Department of Quantitative Biomedicine ,030217 neurology & neurosurgery ,Nuclear localization sequence - Abstract
Mutations disrupting the nuclear localization of the RNA-binding protein FUS characterize a subset of amyotrophic lateral sclerosis patients (ALS-FUS). FUS regulates nuclear RNAs, but its role at the synapse is poorly understood. Using super-resolution imaging we determined that the localization of FUS within synapses occurs predominantly near the vesicle reserve pool of presynaptic sites. Using CLIP-seq on synaptoneurosomes, we identified synaptic FUS RNA targets, encoding proteins associated with synapse organization and plasticity. Significant increase of synaptic FUS during early disease in a mouse model of ALS was accompanied by alterations in density and size of GABAergic synapses. mRNAs abnormally accumulated at the synapses of 6-month-old ALS-FUS mice were enriched for FUS targets and correlated with those depicting increased short-term mRNA stability via binding primarily on multiple exonic sites. Our study indicates that synaptic FUS accumulation in early disease leads to synaptic impairment, potentially representing an initial trigger of neurodegeneration., Mutations in the RNA-binding protein FUS contribute to ALS. Here the authors use CLIP-seq on synaptoneurosomes to identify proteins associated with synapse organization and plasticity that are differentially regulated in a knock-in ALS mouse model.
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- 2021
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- View/download PDF
16. LAG3 is not expressed in human and murine neurons and does not modulate α-synucleinopathies
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Pierre De Rossi, Therese W. Herling, Marian Hruska-Plochan, Nora Bengoa-Vergniory, Ronald Melki, Natalie Landeck, Mathias Jucker, Simone Hornemann, Philipp J. Kahle, Rebekah G. Langston, Andrés González-Guerra, Merve Avar, Melanie Barth, Timo Eninger, Lisa M. Häsler, Kelvin C. Luk, Mehtap Bacioglu, Daniel Heinzer, Elena Tantardini, Marc Emmenegger, Tuomas P. J. Knowles, Magdalini Polymenidou, Elena De Cecco, Alice Kaganovich, Matthias Schneider, Naunehal S. Matharu, Mark R. Cookson, Adriano Aguzzi, and Regina Reimann
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Genetically modified mouse ,Synucleinopathies ,0303 health sciences ,LAG3 ,Hippocampal slice ,Biology ,Fibril ,Immune checkpoint ,Cell biology ,03 medical and health sciences ,0302 clinical medicine ,Receptor ,030217 neurology & neurosurgery ,Ex vivo ,030304 developmental biology - Abstract
While the initial pathology of Parkinson’s disease and other α-synucleinopathies is often confined to circumscribed brain regions, it can spread and progressively affect adjacent and distant brain locales. This process may be controlled by cellular receptors of α-synuclein fibrils, one of which was proposed to be the LAG3 immune checkpoint molecule. Here, we analyzed the expression pattern of LAG3 in human and mouse brains. Using a variety of methods and model systems, we found no evidence for LAG3 expression by neurons. While we confirmed that LAG3 interacts with α-synuclein fibrils, the specificity of this interaction appears limited. Moreover, overexpression of LAG3 in cultured human neural cells did not cause any worsening of α-synuclein pathology ex vivo. The overall survival of A53T α-synuclein transgenic mice was unaffected by LAG3 depletion and the seeded induction of α-synuclein lesions in hippocampal slice cultures was unaffected by LAG3 knockout. These data suggest that the proposed role of LAG3 in the spreading of α-synucleinopathies is not universally valid.
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- 2021
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17. Author Reply to Peer Reviews of LAG3 is not expressed in human and murine neurons and does not modulate α-synucleinopathies
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Aguzzi, Adriano, primary, Jucker, Mathias, additional, Polymenidou, Magdalini, additional, Cookson, Mark R., additional, Knowles, Tuomas P. J., additional, Hornemann, Simone, additional, Kahle, Philipp J., additional, Melki, Ronald, additional, Luk, Kelvin, additional, Landeck, Natalie, additional, Matharu, Naunehal S., additional, Herling, Therese W., additional, Häsler, Lisa M., additional, Reimann, Regina, additional, Heinzer, Daniel, additional, Avar, Merve, additional, Gonzalez-Guerra, Andrès, additional, Bengoa-Vergniory, Nora, additional, Kaganovich, Alice, additional, Langston, Rebekah G., additional, Bacioglu, Mehtap, additional, de Rossi, Pierre, additional, Tantardini, Elena, additional, Barth, Melanie, additional, Schneider, Matthias M., additional, Eninger, Timo, additional, Hruska-Plochan, Marian, additional, De Cecco, Elena, additional, and Emmenegger, Marc, additional
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- 2021
- Full Text
- View/download PDF
18. Synaptic FUS accumulation triggers early misregulation of synaptic RNAs in a mouse model of ALS
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Sahadevan, Sonu, primary, Hembach, Katharina M., additional, Tantardini, Elena, additional, Pérez-Berlanga, Manuela, additional, Hruska-Plochan, Marian, additional, Megat, Salim, additional, Weber, Julien, additional, Schwarz, Petra, additional, Dupuis, Luc, additional, Robinson, Mark D., additional, De Rossi, Pierre, additional, and Polymenidou, Magdalini, additional
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- 2021
- Full Text
- View/download PDF
19. Synaptic accumulation of FUS triggers age-dependent misregulation of inhibitory synapses in ALS-FUS mice
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Katharina M. Hembach, Elena Tantardini, Sonu Sahadevan, Mark D. Robinson, Marian Hruska-Plochan, Petra Schwarz, Julien Weber, Manuela Pérez-Berlanga, Luc Dupuis, Magdalini Polymenidou, and P. de Rossi
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Synapse ,Glutamatergic ,Neurodegeneration ,medicine ,GABAergic ,RNA ,Biology ,Amyotrophic lateral sclerosis ,medicine.disease ,Synapse organization ,Nuclear localization sequence ,Cell biology - Abstract
FUS is a primarily nuclear RNA-binding protein with important roles in RNA processing and transport. FUS mutations disrupting its nuclear localization characterize a subset of amyotrophic lateral sclerosis (ALS-FUS) patients, through an unidentified pathological mechanism. FUS regulates nuclear RNAs, but its role at the synapse is poorly understood. Here, we used super-resolution imaging to determine the physiological localization of extranuclear, neuronal FUS and found it predominantly near the vesicle reserve pool of presynaptic sites. Using CLIP-seq on synaptoneurosome preparations, we identified synaptic RNA targets of FUS that are associated with synapse organization and plasticity. Synaptic FUS was significantly increased in a knock-in mouse model of ALS-FUS, at presymptomatic stages, accompanied by alterations in density and size of GABAergic synapses. RNA-seq of synaptoneurosomes highlighted age-dependent dysregulation of glutamatergic and GABAergic synapses. Our study indicates that FUS accumulation at the synapse in early stages of ALS-FUS results in synaptic impairment, potentially representing an initial trigger of neurodegeneration.
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- 2020
- Full Text
- View/download PDF
20. Synaptic FUS accumulation triggers early misregulation of synaptic RNAs in a mouse model of ALS
- Author
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Sahadevan, Sonu, Hembach, Katharina M; https://orcid.org/0000-0001-5041-6205, Tantardini, Elena; https://orcid.org/0000-0001-9189-3390, Pérez-Berlanga, Manuela; https://orcid.org/0000-0001-9064-9724, Hruska-Plochan, Marian; https://orcid.org/0000-0002-9253-4362, Megat, Salim, Weber, Julien, Schwarz, Petra; https://orcid.org/0000-0003-1686-8624, Dupuis, Luc; https://orcid.org/0000-0002-0902-5824, Robinson, Mark D; https://orcid.org/0000-0002-3048-5518, De Rossi, Pierre; https://orcid.org/0000-0002-2356-4269, Polymenidou, Magdalini; https://orcid.org/0000-0003-1271-9445, Sahadevan, Sonu, Hembach, Katharina M; https://orcid.org/0000-0001-5041-6205, Tantardini, Elena; https://orcid.org/0000-0001-9189-3390, Pérez-Berlanga, Manuela; https://orcid.org/0000-0001-9064-9724, Hruska-Plochan, Marian; https://orcid.org/0000-0002-9253-4362, Megat, Salim, Weber, Julien, Schwarz, Petra; https://orcid.org/0000-0003-1686-8624, Dupuis, Luc; https://orcid.org/0000-0002-0902-5824, Robinson, Mark D; https://orcid.org/0000-0002-3048-5518, De Rossi, Pierre; https://orcid.org/0000-0002-2356-4269, and Polymenidou, Magdalini; https://orcid.org/0000-0003-1271-9445
- Abstract
Mutations disrupting the nuclear localization of the RNA-binding protein FUS characterize a subset of amyotrophic lateral sclerosis patients (ALS-FUS). FUS regulates nuclear RNAs, but its role at the synapse is poorly understood. Using super-resolution imaging we determined that the localization of FUS within synapses occurs predominantly near the vesicle reserve pool of presynaptic sites. Using CLIP-seq on synaptoneurosomes, we identified synaptic FUS RNA targets, encoding proteins associated with synapse organization and plasticity. Significant increase of synaptic FUS during early disease in a mouse model of ALS was accompanied by alterations in density and size of GABAergic synapses. mRNAs abnormally accumulated at the synapses of 6-month-old ALS-FUS mice were enriched for FUS targets and correlated with those depicting increased short-term mRNA stability via binding primarily on multiple exonic sites. Our study indicates that synaptic FUS accumulation in early disease leads to synaptic impairment, potentially representing an initial trigger of neurodegeneration.
- Published
- 2021
21. LAG3 is not expressed in human and murine neurons and does not modulate α-synucleinopathies
- Author
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Emmenegger, Marc, primary, De Cecco, Elena, additional, Hruska-Plochan, Marian, additional, Eninger, Timo, additional, Schneider, Matthias M., additional, Barth, Melanie, additional, Tantardini, Elena, additional, de Rossi, Pierre, additional, Bacioglu, Mehtap, additional, Langston, Rebekah G., additional, Kaganovich, Alice, additional, Bengoa-Vergniory, Nora, additional, Gonzalez-Guerra, Andrès, additional, Avar, Merve, additional, Heinzer, Daniel, additional, Reimann, Regina, additional, Häsler, Lisa M., additional, Herling, Therese W., additional, Matharu, Naunehal S., additional, Landeck, Natalie, additional, Luk, Kelvin, additional, Melki, Ronald, additional, Kahle, Philipp J., additional, Hornemann, Simone, additional, Knowles, Tuomas P. J., additional, Cookson, Mark R., additional, Polymenidou, Magdalini, additional, Jucker, Mathias, additional, and Aguzzi, Adriano, additional
- Published
- 2021
- Full Text
- View/download PDF
22. Synaptic accumulation of FUS triggers age-dependent misregulation of inhibitory synapses in ALS-FUS mice
- Author
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Sahadevan, Sonu, primary, Hembach, Katharina M., additional, Tantardini, Elena, additional, Pérez-Berlanga, Manuela, additional, Hruska-Plochan, Marian, additional, Weber, Julien, additional, Schwarz, Petra, additional, Dupuis, Luc, additional, Robinson, Mark D., additional, De Rossi, Pierre, additional, and Polymenidou, Magdalini, additional
- Published
- 2020
- Full Text
- View/download PDF
23. Synaptic accumulation of FUS triggers age-dependent misregulation of inhibitory synapses in ALS-FUS mice
- Author
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Sahadevan, Sonu, Hembach, Katharina M, Tantardini, Elena, Pérez-Berlanga, Manuela, Hruska-Plochan, Marian, Weber, Julien, Schwarz, Petra, Dupuis, Luc, Robinson, Mark D, De Rossi, Pierre, Polymenidou, Magdalini, Sahadevan, Sonu, Hembach, Katharina M, Tantardini, Elena, Pérez-Berlanga, Manuela, Hruska-Plochan, Marian, Weber, Julien, Schwarz, Petra, Dupuis, Luc, Robinson, Mark D, De Rossi, Pierre, and Polymenidou, Magdalini
- Abstract
FUS is a primarily nuclear RNA-binding protein with important roles in RNA processing and transport. FUS mutations disrupting its nuclear localization characterize a subset of amyotrophic lateral sclerosis (ALS-FUS) patients, through an unidentified pathological mechanism. FUS regulates nuclear RNAs, but its role at the synapse is poorly understood. Here, we used super-resolution imaging to determine the physiological localization of extranuclear, neuronal FUS and found it predominantly near the vesicle reserve pool of presynaptic sites. Using CLIP-seq on synaptoneurosome preparations, we identified synaptic RNA targets of FUS that are associated with synapse organization and plasticity. Synaptic FUS was significantly increased in a knock-in mouse model of ALS-FUS, at presymptomatic stages, accompanied by alterations in density and size of GABAergic synapses. RNA-seq of synaptoneurosomes highlighted age-dependent dysregulation of glutamatergic and GABAergic synapses. Our study indicates that FUS accumulation at the synapse in early stages of ALS-FUS results in synaptic impairment, potentially representing an initial trigger of neurodegeneration.
- Published
- 2020
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