10 results on '"Sahadevan, Sonu"'
Number of results to display per page
Search Results
2. Loss of TDP‐43 oligomerization or RNA binding elicits distinct aggregation patterns
- Author
-
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. Identification of RNA–RBP Interactions in Subcellular Compartments by CLIP-Seq
- Author
-
Sahadevan, Sonu, primary, Pérez-Berlanga, Manuela, additional, and Polymenidou, Magdalini, additional
- Published
- 2022
- Full Text
- View/download PDF
4. A model of human neural networks reveals NPTX2 pathology in ALS and FTLD
- Author
-
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
5. Loss of TDP-43 oligomerization or RNA binding elicits distinct aggregation patterns
- Author
-
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
6. TDP-43 oligomerization and RNA binding are codependent but their loss elicits distinct pathologies
- Author
-
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
7. Identification of RNA–RBP Interactions in Subcellular Compartments by CLIP-Seq
- Author
-
Matějů, Daniel, Chao, Jeffrey A, Matějů, D ( Daniel ), Chao, J A ( Jeffrey A ), Sahadevan, Sonu, Pérez-Berlanga, Manuela, Polymenidou, Magdalini, Matějů, Daniel, Chao, Jeffrey A, Matějů, D ( Daniel ), Chao, J A ( Jeffrey A ), Sahadevan, Sonu, Pérez-Berlanga, Manuela, and Polymenidou, Magdalini
- Abstract
Cross-linking immunoprecipitation and high-throughput sequencing (CLIP-seq) allows the identification of RNA targets bound by a specific RNA-binding protein (RBP) in in vivo and ex vivo experimental models with high specificity. Due to the little RNA yield obtained after cross-linking, immunoprecipitation, polyacrylamide gel electrophoresis, membrane transfer, and RNA extraction, CLIP-seq is usually performed from relatively large amounts of starting material, like cell lysates or tissue homogenates. However, RBP binding of its specific RNA targets depends on its subcellular localization, and a different set of RNAs may be bound by the same RBP within distinct subcellular sites. To uncover these RNA subsets, preparation of CLIP-seq libraries from specific subcellular compartments and comparison to CLIP-seq datasets from total lysates is necessary, yet there are currently no available protocols for this. Here we describe the adaptation of CLIP-seq to identify the specific RNA targets of an RBP (FUS) at a small subcompartment, that is, neuronal synapses, including subcompartment isolation, RBP–RNA complex enrichment, and upscaling steps.
- Published
- 2022
8. TDP-43 oligomerization and RNA binding are codependent but their loss elicits distinct pathologies
- Author
-
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
9. TDP-43 oligomerization and RNA binding are codependent but their loss elicits distinct pathologies
- Author
-
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
10. Identification of RNA–RBP Interactions in Subcellular Compartments by CLIP-Seq
- Author
-
Sahadevan, Sonu, Pérez-Berlanga, Manuela, Polymenidou, Magdalini, University of Zurich, Matějů, Daniel, Chao, Jeffrey A, and Polymenidou, Magdalini
- Subjects
1311 Genetics ,1312 Molecular Biology ,610 Medicine & health ,11493 Department of Quantitative Biomedicine - Published
- 2022
- Full Text
- View/download PDF
Catalog
Books, media, physical & digital resources
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.