Vilchez, David - C 16

Correction of alterations in the ubiquitinated proteome to prevent age-related neurodegenerative diseases

Prof. Dr. David Vilchez
Prof. Dr. David Vilchez

CECAD Research Center

CMMC - PI - C 16

CMMC Profile Page

Curriculum Vitae (CV)

Publications on PubMed

CECAD Research Center

Joseph-Stelzmann-Str. 26

50931 Cologne

Introduction

Life expectancy has risen remarkably and the number of older people will continue to increase. Aging is a major risk factor for neurodegenerative diseases that involve protein aggregation, such as amyotrophic lateral sclerosis (ALS), Huntington’s (HD), Parkinson’s and Alzheimer’s.

We have discovered that aging induces a rewiring of the ubiquitinated proteome, whereby hundreds of proteins undergo changes in ubiquitin modifications. Given the central role of ubiquitination in cell function, a functional study of these alterations can lead to novel modifiers of aging and disease. Together, our approach that combines state-of-the-art proteomics, human iPSC-disease modelling and genetics in the model organism C. elegans can provide insights into converging strategies for preventing and/or treating different age-related neurodegenerative disorders.

Lowering the accumulation of EPS-8 protein during aging prevents alterations in myosin filaments. Myosin heavy chain tagged to GFP indicates destabilization of myosin filaments in muscle cells during aging of C. elegans, whereas knockdown of deubiquitinated eps-8 during adulthood maintains organization of the myosin network. Scale bar, 20 μm.
Motor neurons derived from ALS patient-iPSCs exhibit disease-related phenotypes after 2 weeks in culture. Immunocytochemistry of human motor neurons derived from control and ALS-iPSCs expressing the FUSP525L mutant variant. Apoptotic cells were stained with anti-cleaved caspase-3 antibody. MAP2 and Hoechst 33342 were used as markers of neurons and nuclei, respectively. Scale bar: 20 μm.

Clinical Relevance

Aging causes a progressive loss of physiological integrity, which can trigger the development of multiple pathologies that remain incurable.  As such, our ever-aging society presents a challenge from the increasing prevalence of age-related diseases. Our innovative approach will define targets to slow down aging and prevent age-related neurodegenerative diseases. Thus, our project can have important implications for multi-disease prevention and be of enormous benefit for our ever-aging society.

Approach

  • We seek to understand how protein homeostasis (proteostasis) and cell non-autonomous responses modulate stem cell function, organismal aging, and the onset of age-related neurodegenerative diseases to uncover mechanisms of regeneration and healthspan extension. 
  • In our lab, we use an innovative approach that combines state-of-the-art proteomics, human stem cell research, iPSC-disease modelling and genetics in the model organism C. elegans.  

  1. H. Alirzayeva, R. Loureiro, S. Koyuncu, F. Hommen, Y. Nabawi, W.H. Zhang, T.T.P. Dao, M. Wehrmann, H.J. Lee, and D. Vilchez (2024). ALS-FUS mutations cause abnormal PARylation and histone H1.2 interaction, leading to pathological changes. Cell Reports43:114626.

  2. X. Li, I. Hernandez, S. Koyuncu, B. Kis, M. Häggblad, L. Lidemalm, A.A. Abbas, S. Bendegúz, A. Göblös, L. Brautigam, J.J. Lucas, J. Carreras-Puigvert, D. Hühn, K. Pircs, D. Vilchez, and O. Fernandez-Capetillo (2024). The anti-leprosy drug clofazimine reduces polyQ toxicity through activation of PPARγ. EBioMedicine 103:105124.

  3. E. Llamas, S. Koyuncu, H.J. Lee, M. Wehrmann, R. Gutierrez-Garcia, N. Dunken, N. Charura, S. Torres-Montilla, E. Schlimgen, A.M. Mandel, E. Boelen-Theile, J. Grossbach, P. Wagle, B. Schermer, T. Benzing, A. Beyer, P. Pulido, M. Rodriguez-Concepcion, A. Zuccaro, and D.Vilchez (2023). In planta expression of human polyQ-expanded huntingtin fragment reveals mechanisms to prevent disease-related protein aggregation. Nature Aging 3: 1345-1357 (cover).

  4. H.J. Lee, H. Alirzayeva, S. Koyuncu, A. Rueber, A. Noormohammadi, and D. Vilchez (2023). Cold temperature extends longevity and prevents disease-related protein aggregation through PA28γ-induced proteasomes. Nature Aging 3: 546-566.

  5. R. Gutierrez-Garcia, S. Koyuncu, F. Hommen, S. Bilican, H.J. Lee, A. Fatima, and D. Vilchez (2023). G3BP1-dependent mechanism suppressing protein aggregation in Huntington’s models and its demise upon stress granule assembly. Human Molecular Genetics 32: 1607-1621.

  6. M. Wehrmann and D. Vilchez (2023). The emerging roles and therapeutic implications of bacterial and parasitic deubiquitinating enzymes. Frontiers in Immunology14:1303072.

  7. N. Ruiz-Solaní, J. Salguero-Linares, L. Armengot, J. Santos, I. Pallarès, K.P. van Midden, U.J. Phukkan, S. Koyuncu, J. Borràs-Bisa, L. Li, C. Popa, F. Eisele, A.M. Eisele-Bürger, S.M. Hill, E. Gutiérrez-Beltrán, T. Nyström, V. Valls, E. Llamas, D. Vilchez, M. Klemenčič, S. Ventura, and N.S. Coll (2023). Arabidopsis metacaspase MC1 localizes in stress granules, clears protein aggregates and delays senescence. Plant Cell35: 3325-3344. 

  8. F. Kohle, R. Ackfeld, F. Hommen, I. Klein, M.K.R. Svačina, C. Schneider, G.R. Fink, M. Barham, D. Vilchez, H.C. Lehmann (2023). Kinesin-5 inhibition improves neural regeneration in experimental autoimmune neuritis. Journal of Neuroinflammation20: 139. 

  9. K. Voelkl, S. Gutiérrez-Ángel, S. Keeling, S. Koyuncu, M. da Silva Padilha, D. Feigenbutz, T. Arzberger, D. Vilchez, R. Klein, and I. Dudanova (2023). Neuroprotective effects of hepatoma-derived growth factor in models of Huntington's disease. Life Science Alliance6:e202302018.

  10. A. Johns, R. Higuchi-Sanabria#, M.A. Thorwald#, and D. Vilchez# (2023). A tale of two pathways: regulation of proteostasis by UPRmt and MDPs. Current Opinion in Neurobiology 78: 102673. #These authors share senior authorship. 

  11. W.H. Zhang, S.  Koyuncu#, and D. Vilchez# (2022). Insights into the links between proteostasis and aging from C. elegans. Frontiers in Aging: doi.org/10.3389/fragi.2022.854157. #These authors share senior authorship.

  12. V. Balaji, L. Müller, R. Lorenz, E. Kevei, W.H. Zhang, U. Santiago, J. Gebauer, E. Llamas, D. Vilchez, C.J. Camacho, W. Pokrzywa, and T. Hoppe (2022). A dimer-monomer switch controls CHIP-dependent substrate ubiquitylation and processing. Molecular Cell82: 3239-3254.

  13. S. Koyuncu, R. Loureiro, H.J. Lee, P. Wagle, M. Krueger and D. Vilchez (2021). Rewiring of the ubiquitinated proteome determines ageing in C. elegans. Nature 596: 285-290.

  14. G. Calculli, H.J. Lee, K. Shen, U. Pham, M. Herholz, A. Trifunovic, A. Dillin and D. Vilchez (2021). Systemic regulation of mitochondria by germline proteostasis prevents protein aggregation in the soma of C. elegans. Science Advances 7: eabg3012.

  15. E. Llamas, S. Torres-Montilla, H.J. Lee, M.V. Barja, E. Schlimgen, N. Dunken, P. Wagle, W. Werr, A. Zuccaro, M. Rodriguez-Concepcion and D. Vilchez (2021). The intrinsic chaperone network of Arabidopsis stem cells confers protection against proteotoxic stress. Aging Cell 20: e13446. 

  16. F. Hommen, S. Bilican and D. Vilchez (2021). Protein clearance strategies for disease intervention. Journal of Neural Transmission 129: 141-172.

  17. S. Sarroca, A. Gatius, E. Rodríguez-Farré, D. Vilchez, M. Pallàs, C. Griñán-Ferré, C. Sanfeliu and R. Corpas (2021). Resveratrol confers neuroprotection against high-fat diet in a mouse model of Alzheimer's disease. The Journal of Nutritional Biochemistry 89: 108569.

  18. E. Llamas, H. Alirzayeva, R. Loureiro and D. Vilchez (2020). The intrinsic proteostasis network of stem cells. Current Opinion in Cell Biology 67: 46-55. 

  19. A. Fatima, D. Irmak, A. Noormohammadi, M.M. Rinschen, A. Das, O. Leidecker, C. Schindler, V. Sánchez-Gaya, P. Wagle, W. Pokrzywa, T. Hoppe, A. Rada-Iglesias and D. Vilchez (2020). The ubiquitin-conjugating enzyme UBE2K determines neurogenic potential through histone H3 in human embryonic stem cells. Communications Biology3: 262. 

  20. A. Thiruvalluvan, E. P. de Mattos, J.F. Brunsting, R. Bakels, D. Serlidaki, L. Barazzuol, P. Conforti, A. Fatima, S. Koyuncu, E. Cattaneo, D. Vilchez, S. Bergink, E. HWG Boddeke, S. Copray and H.H. Kampinga (2020). DNAJB6, a key factor in neuronal sensitivity to amyloidogenesis. Molecular Cell78: 346-358. 

  21. I. Saez, J. Gerbracht, S. Koyuncu, H.J. Lee, M. Horn, V. Kroef, M. Denzel, C. Dieterich, N. Gehring and D. Vilchez (2020). The E3 ubiquitin ligase UBR5 interacts with the H/ACA ribonucleoprotein complex and regulates ribosomal RNA biogenesis in embryonic stem cells. FEBS Letters594: 175-188. 

  22. C. Kumsta, J.T. Chang, R. Lee, E.P. Tan, Y. Yang, R. Loureiro, E.H. Choy, S.H.Y. Lim, I. Saez, A. Springhorn, T. Hoppe, D. Vilchez and M. Hansen (2019). The autophagy receptor p62/SQST-1 promotes proteostasis and longevity in C. elegans by inducing autophagy. Nature Communications 10: 5648. 

  23. H.J. Lee, A. Noormohammadi, S. Koyuncu, G. Calculli, M. Simic, M. Herholz, A. Trifunovic and D. Vilchez (2019). Prostaglandin signals from adult germline stem cells delay somatic ageing of Caenorhabditis elegans. Nature Metabolism1: 790-810 (cover). 

  24. A. Fatima, R. Gutierrez-Garcia and D. Vilchez (2019). Induced pluripotent stem cells from Huntington's disease patients: a promising approach to define and correct disease-related alterations. Neural Regeneration Research 14: 769-770.

  25. D. Irmak, A. Fatima, R. Gutierrez-Garcia, M. Rinschen, P. Wagle, J. Altmüller, L. Arrigoni, B. Hummel, C. Klein, C.K. Frese, R. Sawarkar, A. Rada-Iglesias and D. Vilchez (2018). Mechanism suppressing H3K9 trimethylation in pluripotent stem cells and its demise by polyQ-expanded huntingtin mutations. Human Molecular Genetics 27: 4117-4134.

  26. S. Koyuncu, I. Saez, H.J. Lee, R. Gutierrez-Garcia, W. Pokrzywa, A. Fatima, T. Hoppe and D. Vilchez (2018). The ubiquitin ligase UBR5 suppresses proteostasis collapse in pluripotent stem cells from Huntington’s disease patients. Nature Communications 9: 2886. 

  27. I. Gonçalves, J. Brecht, M. Thelen, W. Rehorst, M. Peters, H.J. Lee, S. Motameny, L. Torres-Benito, D. Ebrahimi-Fakhari, N. Kononenko, J. Altmüller, D. Vilchez, M. Sahin, B. Wirth and M.J. Kye (2018). Neuronal activity regulates DROSHA via autophagy in Spinal Muscular Atrophy. Scientific Reports 8: 7907.

  28. I. Saez, S. Koyuncu, R. Gutierrez-Garcia, C. Dieterich and D. Vilchez (2018). Insights into the ubiquitin-proteasome system of human embryonic stem cells. Scientific Reports 8: 4092. 

  29. H.J. Lee, D. Bartsch, C. Xao, S. Guerrero, G. Ahuja, C. Schindler, J.M. Moresco, J.R. Yates III, F. Gebauer, H. Bazzi, C. Dieterich, L. Kurian and D. Vilchez (2017). A post-transcriptional program coordinated by CSDE1 prevents intrinsic neural differentiation of human embryonic stem cells. Nature Communications 8: 1456. 

  30. A. Noormohammadi, G. Calculli, R. Gutierrez-Garcia, A. Khodokarami, S. Koyuncu and D. Vilchez (2017). Mechanisms of protein homeostasis (proteostasis) maintain stem cell identity in mammalian pluripotent stem cells. Cellular and Molecular Life Sciences 75: 275-290. 

  31. S. Koyuncu, A. Fatima, R. Gutierrez-Garcia and D. Vilchez (2017). Proteostasis of huntingtin in health and disease. International Journal of Molecular Sciences 18: E1568. 

  32. A. Noormohammadi, A. Khodakarami, R. Gutierrez-Garcia, H.J. Lee, S. Koyuncu, T. König, C. Schindler, I. Saez, A. Fatima, C. Dieterich and D. Vilchez (2016). Somatic increase of CCT8 mimics proteostasis of human pluripotent stem cells and extends C. elegans lifespan. Nature Communications 7: 13649. 

  33. H.J. Lee, R. Gutierrez-Garcia and D. Vilchez (2016). Embryonic stem cells: A novel approach to study proteostasis? FEBS Journal 284: 391-398. 

  34. M.M. Rinschen, P. Bharill, X. Wu, P. Kohli, M.J. Reinert, O. Kretz, I. Saez, B. Schermer, M. Höhne, M.P. Bartram, S. Aravamudhan, B.R. Brooks, D. Vilchez, T.B. Huber, R.U. Müller, M. Krüger and T. Benzing (2016). The ubiquitin ligase Ubr4 controls stability of podocin/MEC-2 supercomplexes. Human Molecular Genetics25: 1328-1344. 

  35. S. Koyuncu, D. Irmak, I. Saez and D. Vilchez (2015). Defining the general principles of stem cell aging: lessons from organismal models. Current Stem Cell Reports1: 162-169. 

  36. D. Vilchez, I. Saez and A. Dillin (2014). The role of protein clearance mechanisms in organismal ageing and age-related diseases. Nature Communications 5: 5659. 

  37. A. Khodakarami, I. Saez, J. Mels and D. Vilchez (2015). Mediation of organismal aging and somatic proteostasis by the germline. Frontiers in Molecular Biosciences 2: 1-7. 

  38. I. Saez and D. Vilchez (2015). Protein clearance mechanisms and their demise in age-related diseases. AIMS Molecular Science 2: 1-21. 

  39. I. Saez and D. Vilchez (2014). The mechanistic links between proteasome activity, aging and age-related diseases. Current Genomics 15: 38-51. 

  40. D. Vilchez#, M. Simic# and A. Dillin (2014). Proteostasis and aging of stem cells. Trends in Cell Biology24: 161-170. #These authors contributed equally to this work. 

  41. D. Vilchez, L. Boyer, M. Lutz, C. Merkwirth, I. Morantte, C. Tse, B. Spencer, L. Page, E. Masliah, W.T. Berggren, F.H. Gage and A. Dillin (2013). FOXO4 is necessary for neural differentiation of human embryonic stem cells. Aging Cell 12: 518-522. 

  42. D. Vilchez, I. Morantte, Z. Liu, P.M. Douglas, C. Merkwirth, A.P. Rodrigues, G. Manning and A. Dillin (2012). RPN-6 determines C. elegans longevity under proteotoxic stress conditions. Nature489: 263-268. 

  43. D. Vilchez, L. Boyer, I. Morantte, M. Lutz, C. Merkwirth, D. Joyce, B. Spencer, L. Page, E. Masliah, F.H. Gage and A. Dillin (2012). Increased proteasome activity in human embryonic stem cells is regulated by PSMD11. Nature489: 304-308. 

  44. M.C. Solaz-Fuster, J.V. Gimeno-Alcañiz, S. Ros, S, M.E. Fernández-Sánchez, B. García-Fojeda, O. Criado-García, D.Vilchez, J. Domínguez, M. García-Rocha, M. Sánchez-Piris, C. Aguado, E. Knecht, J. Serratosa, J.J. Guinovart, P. Sanz and S. Rodríguez de Córdoba (2008). Regulation of glycogen synthesis by the laforin-malin complex is modulated by the AMP-activated protein kinase pathway. Human Molecular Genetics17: 667-78. 

  45. D. Vilchez, S. Ros, L. Pujadas, D. Cifuentes, J. Vallès, B. Garcia-Fojeda, O. Criado-García, E. Fernández-Sánchez, M. Medraño-Fernández, J. Domínguez, M. García-Rocha, E. Soriano, S. Rodríguez de Córdoba and J.J. Guinovart (2007). Mechanism suppressing glycogen synthesis in neurons and its demise in progressive myoclonus epilepsy. Nature Neuroscience10: 1407-13. 

  46. J. Sebastià, M. Pertusa, D.Vilchez, A.M. Planas, R. Verbeek, E. Rodríguez-Farré, R. Cristòfol and C. Sanfeliu (2006). Carboxyl-terminal fragment of amyloid precursor protein and hydrogen peroxide induce neuronal cell death through different pathways. Journal of Neural Transmission113: 1837-1845. 

  47. J. Sebastià, R.M. Cristòfol, M. Pertusa, D.Vilchez, N. Torán, S. Barambio, E. Rodríguez-Farré and C. Sanfeliu (2004). Down’s syndrome astrocytes have greater antioxidant capacity than euploid astrocytes. European Journal of Neuroscience20: 2355-2366. 

  48. R.M. Cristòfol, S. Gassó, D. Vilchez, M. Pertusa, E. Rodríguez-Farré and C. Sanfeliu (2004). Neurotoxic effects of trimethyltin and triethyltin on human fetal neuron and astrocyte cultures: A comparative study with rat neuronal cultures and human cell lines. Toxicology Letters152: 35-46. 

Lab Website

For more information (research, lab members etc.), please check Vilchez Lab. 

Affiliations

Publication Record on PubMed

2024 (up to June)
  • Koyuncu S, Loureiro R, Lee HJ, Wagle P, Krueger M, Vilchez D. Author Correction: Rewiring of the ubiquitinated proteome determines ageing in C. elegans. Nature. 2024 Feb;626(8001):E20. doi: 10.1038/s41586-024-07168-8. Erratum for: Nature. 2021 Aug;596(7871):285-290. doi: 10.1038/s41586-021-03781-z. PMID: 38347194; PMCID: PMC10901727.
2023
  • Gutierrez-Garcia R, Koyuncu S, Hommen F, Bilican S, Lee HJ, Fatima A, and Vilchez D (2023). G3BP1-dependent mechanism suppressing protein aggregation in Huntington's models and its demise upon stress granule assembly. Hum Mol Genet 32, 1607-1621. doi:10.1093/hmg/ddac304.
     
  • Johns A, Higuchi-Sanabria R, Thorwald MA, and Vilchez D (2023). A tale of two pathways: Regulation of proteostasis by UPR(mt) and MDPs. Curr Opin Neurobiol 78, 102673. doi:10.1016/j.conb.2022.102673.
     
  • Kohle F, Ackfeld R, Hommen F, Klein I, Svacina MKR, Schneider C, Fink GR, Barham M, Vilchez D, and Lehmann HC (2023). Kinesin-5 inhibition improves neural regeneration in experimental autoimmune neuritis. J Neuroinflammation 20, 139. doi:10.1186/s12974-023-02822-w
     
  • Lee HJ, Alirzayeva H, Koyuncu S, Rueber A, Noormohammadi A, and Vilchez D (2023). Cold temperature extends longevity and prevents disease-related protein aggregation through PA28gamma-induced proteasomes. Nat Aging 3, 546-566. doi:10.1038/s43587-023-00383-4.
     
  • Llamas E, Koyuncu S, Lee HJ, Wehrmann M, Gutierrez-Garcia R, Dunken N, Charura N, Torres-Montilla S, Schlimgen E, Mandel AM, Theile EB, Grossbach J, Wagle P, Lackmann JW, Schermer B, Benzing T, Beyer A, Pulido P, Rodriguez-Concepcion M, Zuccaro A, and Vilchez D (2023). In planta expression of human polyQ-expanded huntingtin fragment reveals mechanisms to prevent disease-related protein aggregation. Nat Aging 3, 1345-1357. doi:10.1038/s43587-023-00502-1.
     
  • Ruiz-Solani N, Salguero-Linares J, Armengot L, Santos J, Pallares I, van Midden KP, Phukkan UJ, Koyuncu S, Borras-Bisa J, Li L, Popa C, Eisele F, Eisele-Burger AM, Hill SM, Gutierrez-Beltran E, Nystrom T, Valls M, Llamas E, Vilchez D, Klemencic M, Ventura S, and Coll NS (2023). Arabidopsis metacaspase MC1 localizes in stress granules, clears protein aggregates, and delays senescence. Plant Cell 35, 3325-3344. doi:10.1093/plcell/koad172.
     
  • Voelkl K, Gutierrez-Angel S, Keeling S, Koyuncu S, da Silva Padilha M, Feigenbutz D, Arzberger T, Vilchez D, Klein R, and Dudanova I (2023). Neuroprotective effects of hepatoma-derived growth factor in models of Huntington's disease. Life Sci Alliance 6. doi:10.26508/lsa.202302018.
     
  • Wehrmann M, and Vilchez D (2023). The emerging role and therapeutic implications of bacterial and parasitic deubiquitinating enzymes. Front Immunol 14, 1303072. doi:10.3389/fimmu.2023.1303072.

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