Carmen Nussbaum

Current GSN students: 

Keywords: neurodegenerative diseases, proteostasis, aging, prion-like spreading

Research methods: Our methods range from confocal microscopy, genetics (e.g. CRISPR), cell biology and biochemistry to systems analysis (using ribosome profiling), mainly in C. elegans, but also in mammalian cell culture. The nematode is easily genetically manipulated and its transparency allows observation of the intercellular spreading of fluorescently labeled disease proteins in an intact living organism. Moreover, its short and defined lifespan facilitates studying the impact of aging on cellular protein homeostasis and neurodegeneration.

Brief research description: My group studies the cellular and molecular mechanisms of aging and age-related neurodegenerative diseases, such as Alzheimer‘s disease or Parkinson’s disease. We use the model organism Caenorhabditis elegans and human cell culture models to investigate the propagation and intercellular spreading of disease-linked proteins, such as alpha-synuclein and Tau. Our recent studies showed that the intercellular spreading of alpha-synuclein triggers endo-lysosomal rupture in receiving cells (Sandhof et al., Autophagy, 2020). In a genome-wide RNAi screen we have now identified genes that affect lysosomal integrity during aging, which we are currently characterizing (unpublished). In addition, we demonstrated that chaperone-mediated disaggregation of amyloid protein aggregates generates toxic protein species, which might play a role in the progression of neurodegenerative diseases (Tittelmeier et al., EMBO J, 2020; Nachman et al., JBC, 2020; Tittelmeier et al., Commun Biol, 2022). Furthermore, we have established cell-type specific ribosome profiling in C. elegans to identify cell type specific factors involved in spreading and selective vulnerability (unpublished).

Selected publications:
1. Tittelmeier J, Druffel-Augustin S., Alik A., Melki R., Nussbaum-Krammer C. Dissecting aggregation and seeding dynamics of α-Syn polymorphs using the phasor approach to FLIM. Commun Biol. 2022 Dec 8;5(1):1345. doi: 10.1038/s42003-022-04289-6.

2. Nachman E, Wentink AS, Madiona K, Bousset L, Katsinelos T, Allinson K, Kampinga H, McEwan WA, Jahn TR, Melki R, Mogk A, Bukau B, and Nussbaum-Krammer C. Disassembly of Tau Fibrils by the Human Hsp70 Disaggregation Machinery Generates Small Seeding-Competent Species. J Biol Chem. 2020 Jul 10;295(28):9676-9690. doi: 10.1074/jbc.RA120.013478.

3. Tittelmeier J, Sandhof CA, Ries HM, Druffel-Augustin S, Klemmer A, Mogk A, Bukau B, Nussbaum-Krammer C. The HSP110/HSP70 disaggregation system generates spreading‐competent toxic α-synuclein species. EMBO J. 2020 Jul 1;39(13):e103954. doi: 10.15252/embj.2019103954. Epub 2020 May 25.

4. Sandhof CA, Hoppe SO, Druffel-Augustin S, Gallrein C, Kirstein J, Voisine C, Nussbaum-Krammer C. Reducing Insulin/IGF1 Signaling Protects Against Non-Cell Autonomous Vesicle Rupture Caused by SNCA Spreading. Autophagy 2020 May;16(5):878-899. doi:10.1080/15548627.2019.1643657.

5. Wentink A, Nussbaum-Krammer, C, Bukau B. Modulation of amyloid states by molecular chaperones. Book chapter in “Protein Homeostasis”, 2nd Edition. Cold Spring Harbor Perspectives in Biology. 2019 Jul (ISBN: 978-1-621822-96-7).