Center for Molecular Medicine Cologne

Vilchez, David - C 16

Defining modulators of RNA-binding protein aggregation for intervention of the neurodegenerative disease Amyotrophic Lateral Sclerosis


While the global incidence of ALS has increased over the years, the molecular mechanisms of the disease remain largely unknown. Our innovative approach has the potential to uncover the converging mechanisms by which mutations in FUS, TDP-43 and C9orf72 result in ALS-associated protein aggregation and degeneration of motor neurons. Thus, our project can lead to novel therapeutic strategies for ALS.

Amyotrophic lateral sclerosis (ALS) is the third most common neurodegenerative disorder and remains incurable. Since aging is a major risk factor for the disease, the number of individuals diagnosed with ALS will rise by 69% in 2040 due to population aging. Aging is characterized by the demise of intracellular pathways that maintain cellular integrity, such as protein homeostasis (proteostasis). In ALS, motor neurons accumulate pathological protein aggregates and degenerate during aging.
To define how aging triggers ALS and diminish age as a risk factor, we proposed a series of ground-breaking approaches combining patient-derived induced pluripotent stem cells (iPSCs) with genetics in the model organism C. elegans. First, we performed an integrated analysis to identify intracellular modulators of pathological protein aggregation induced by different ALS-related mutant proteins in motor neurons derived from ALS-iPSCs. Then, we screened whether these factors modulate protein aggregation and neurotoxicity in ALS C. elegans models expressing the same human mutant variants of our ALS-iPSC lines. After we identified modulators of ALS-related protein aggregation in C. elegans models, we determined their impact in human motor neurons derived from ALS-iPSCs.
Beyond cell autonomous mechanisms, distinct tissues can influence aging of distal organs. In our previous work, we discovered that a rejuvenated germline delays the aging of neurons, opening a new perspective that needed to be explored. In this project, we have now found that a collapse in the proteostasis of C. elegans germline stem cells leads to mitochondrial alterations in neurons through long-range Wnt signaling. Subsequently, mitochondrial alterations in the nervous system increase neuronal aggregation of ALS-related proteins (Calculli et al, Science Advances 2021). Together, our project identified both cell autonomous and non-autonomous modifiers of ALS, providing potential therapeutic targets for the disease.

Figure 1

Our Aims

  1. Defining changes induced by ALS-mutant related proteins

  2. Screen in ALS disease models

  3. Ameliorate protein aggregation in human motor neurons derived from ALS-iPSCs

Previous Work

David Vilchez’s laboratory has made important contributions to our understanding of how human pluripotent stem cells regulate protein quality control.

For instance, his lab found that pluripotent stem cells exhibit up-regulation of specific E3 ubiquitin ligase enzymes to modulate factors required for hESC/iPSC function and self-renewal (Saez et al, Scientific Reports 2018, Saez et al, FEBS Letters 2019). Among them, they found a novel pathway involved in the degradation and modification of histone H3 link with Huntington’s disease (Irmak et al, Human Molecular Genetics 2018, Fatima et al, In revision in Stem Cell Reports).

David’s lab also defined that the E3 ubiquitin ligase UBR5 prevents aggregation of mutant huntingtin in iPSCs derived from Huntington’s disease patients (Koyuncu et al, Nature Communications 2018). In these lines, his lab discovered that human pluripotent stem cells also have enhanced levels of other proteostasis mechanisms to suppress toxic protein aggregation (Noormohammadi et al, Nature Communications 2016). For instance, hESCs/iPSCs have endogenous mechanisms of post-transcriptional regulation and protein synthesis (Lee et al, Nature Communications 2017) as well as protein folding (Noormohammadi et al, Nature Communications 2016).

Importantly, mimicking these proteostasis mechanisms in somatic tissues was sufficient to prolong organismal healthspan and delay age-related diseases in C. elegans models (Koyuncu et al, Nature Communications 2018, Lee et al, Nature Communications 2017, Noormohammadi et al, Nature Communications 2016). Besides its work on proteostasis of stem cells, David’s laboratory has made significant advances on understanding the cell non-autonomous mechanisms by which germ stem cells regulate the fitness of the soma. Importantly, they discovered that germ stem cells communicate with somatic tissues by releasing prostaglandin signals to coordinate extended reproductive capacity with longevity under favourable conditions, without compromising either fertility or organismal healthspan (Lee et al, Nature Metabolism 2019, cover). 

  • Calculli G, Lee HJ, Shen K, Pham U, Herholz M, Trifunovic A, Dillin A, and Vilchez D (2021). Systemic regulation of mitochondria by germline proteostasis prevents protein aggregation in the soma of C. elegans. Sci Adv 7. doi:10.1126/sciadv.abg3012.
  • Koyuncu S, Loureiro R, Lee HJ, Wagle P, Krueger M, and Vilchez D (2021). Rewiring of the ubiquitinated proteome determines ageing in C. elegans. Nature 596, 285-290. doi:10.1038/s41586-021-03781-z.
  • 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 elegansNature Metabolism 1:790-810 (cover).
  • I. Saez, J. Gerbracht, S. Koyuncu, H.J. Lee, M. Horn, V. Kroef, M. Denzel, C. Dieterich, N. Gehring and D. Vilchez (2019). The E3 ubiquitin ligase UBR5 interacts with the H/ACA ribonucleoprotein complex and regulates ribosomal RNA biogenesis in embryonic stem cells. FEBS Letters doi:10.1002/1873-3468.13559.
  • 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.
  • 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.
  • 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 immortal pluripotent stem cells from Huntington’s disease patients. Nature Communications 92886.
  • I. Saez, S. Koyuncu, R. Gutierrez-Garcia, C. Dieterich and D. Vilchez (2018). Modulation of human embryonic stem cell identity by the ubiquitin-proteasome system. Scientific Reports 84092.
  • 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 81456.
  • A. Noormohammadi, G. Calculli, R. Gutierrez-Garcia, A. Khodokarami, S. Koyuncu and D. Vilchez (2017). Mechanisms of protein homeostasis (proteostasis) mantain stem cell identity in mammalian pluripotent stem cells. Cellularand Molecular Life Sciences 75 (2), 275-290.
  • S. Koyuncu, A. Fatima, R. Gutierrez-Garcia and D. Vilchez (2017). Proteostasis of huntingtin in health and disease. International Journal of Molecular Sciences 18 (7), E1568.
  • A. Noormohammadi, A. Khodakarami, R. Gutierrez-Garcia, H.J. Lee, S. Koyuncu, T. König, C. Schindler, I. Saez, A. Fatima, C. Dieterich, D. Vilchez (2016). Somatic increase of CCT8 mimics proteostasis of human pluripotent stem cells and extends C. elegans lifespan. Nature Communications 713649.
  • H.J. Lee, R. Gutierrez-Garcia, D. Vilchez (2016). Embryonic stem cells: A novel approach to study proteostasis? FEBS Journal 284 (3), 391-398.
  • 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 Reports 25(7): 162-169.
  • D. Vilchez, I. Saez and A. Dillin (2014). The role of protein clearance mechanisms in organismal ageing and age-related diseases. Nature Communications 55659.
  • 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(3): 1-7
  • I. Saez and D. Vilchez (2014). The mechanistic links between proteasome activity, aging and age-related diseases. Current Genomics 15(1): 38-51. 
  • D. Vilchez#, M. Simic# and A. Dillin (2014). Proteostasis and aging of stem cells. Trends in Cell Biology 24(3): 161-170. #These authors contributed equally to this work. 
  • 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(3): 518-522.
  • 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. Nature 489(7415): 263-268.
  • 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. Nature 489(7415): 304-308.
  • Hommen F, Bilican S, and Vilchez D (2022). Protein clearance strategies for disease intervention. J Neural Transm (Vienna)129, 141-172. doi:10.1007/s00702-021-02431-y.
  • W.H. Zhang, S.  Koyuncu#, and D. Vilchez# (2022). Insights into the links between proteostasis and aging from C. elegans. Frontiers in Aging: #These authors share senior authorship.
  • Calculli G, Lee HJ, Shen K, Pham U, Herholz M, Trifunovic A, Dillin A, and Vilchez D (2021). Systemic regulation of mitochondria by germline proteostasis prevents protein aggregation in the soma of C. elegans. Sci Adv7. doi:10.1126/sciadv.abg3012.
  • Koyuncu S, Loureiro R, Lee HJ, Wagle P, Krueger M, and Vilchez D (2021). Rewiring of the ubiquitinated proteome determines ageing in C. elegans. Nature596, 285-290. doi:10.1038/s41586-021-03781-z.
  • Llamas E, Torres-Montilla S, Lee HJ, Barja MV, Schlimgen E, Dunken N, Wagle P, Werr W, Zuccaro A, Rodriguez-Concepcion M, and Vilchez D (2021). The intrinsic chaperone network of Arabidopsis stem cells confers protection against proteotoxic stress. Aging Cell20, e13446. doi:10.1111/acel.13446.
  • Hommen F, Bilican S, and Vilchez D (2021). Protein clearance strategies for disease intervention. J Neural Transm (Vienna). doi:10.1007/s00702-021-02431-y.
  • Fatima A, Irmak D, Noormohammadi A, Rinschen MM, Das A, Leidecker O, Schindler C, Sanchez-Gaya V, Wagle P, Pokrzywa W, Hoppe T, Rada-Iglesias A, and Vilchez D (2020). The ubiquitin-conjugating enzyme UBE2K determines neurogenic potential through histone H3 in human embryonic stem cells. Commun Biol 3, 262.
  • Llamas E, Alirzayeva H, Loureiro R, and D. Vilchez (2020). The intrinsic proteostasis network of stem cells. Current Opinion in Cell Biology 67: 46-55.
Prof. Dr. David Vilchez CMMC Cologne
Prof. Dr. David Vilchez

CECAD Research Center

CMMC - PI - C 16

+49 221 478 84172

CECAD Research Center

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50931 Cologne

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Curriculum Vitae (CV)

Publications on PubMed

Publications - David Vilchez

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