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  • Dual Role of Ribosome-Binding Domain of NAC as a Potent Suppressor of Protein Aggregation and Aging-Related Proteinopathies MOLECULAR CELL Shen, K., Gamerdinger, M., Chan, R., Gense, K., Martin, E. M., Sachs, N., Knight, P. D., Schloemer, R., Calabrese, A. N., Stewart, K. L., Leiendecker, L., Baghel, A., Radford, S. E., Frydman, J., Deuerling, E. 2019; 74 (4): 729-+
  • Dual Role of Ribosome-Binding Domain of NAC as a Potent Suppressor of Protein Aggregation and Aging-Related Proteinopathies. Molecular cell Shen, K., Gamerdinger, M., Chan, R., Gense, K., Martin, E. M., Sachs, N., Knight, P. D., Schlomer, R., Calabrese, A. N., Stewart, K. L., Leiendecker, L., Baghel, A., Radford, S. E., Frydman, J., Deuerling, E. 2019

    Abstract

    The nascent polypeptide-associated complex (NAC) is a conserved ribosome-associated protein biogenesis factor. Whether NAC exerts chaperone activity and whether this function is restricted to de novo protein synthesis is unknown. Here, we demonstrate that NAC directly exerts chaperone activity toward structurally diverse model substrates including polyglutamine (PolyQ) proteins, firefly luciferase, and Abeta40. Strikingly, we identified the positively charged ribosome-binding domain in the N terminus of the betaNAC subunit (N-betaNAC) as a major chaperone entity of NAC. N-betaNAC by itself suppressed aggregation of PolyQ-expanded proteins invitro, and the positive charge of this domain was critical for this activity. Moreover, we found that NAC also exerts a ribosome-independent chaperone function invivo. Consistently, we found that a substantial fraction of NAC is non-ribosomal bound in higher eukaryotes. In sum, NAC is a potent suppressor of aggregation and proteotoxicity of mutant PolyQ-expanded proteins associated with human diseases like Huntington's disease and spinocerebellar ataxias.

    View details for PubMedID 30982745

  • Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris. Nature 2018; 562 (7727): 367–72

    Abstract

    Here we present a compendium of single-cell transcriptomic data from the model organism Mus musculus that comprises more than 100,000 cells from 20 organs and tissues. These data represent a new resource for cell biology, reveal gene expression in poorly characterized cell populations and enable the direct and controlled comparison of gene expression in cell types that are shared between tissues, such as T lymphocytes and endothelial cells from different anatomical locations. Two distinct technical approaches were used for most organs: one approach, microfluidic droplet-based 3'-end counting, enabled the survey of thousands of cells at relatively low coverage, whereas the other, full-length transcript analysis based on fluorescence-activated cell sorting, enabled the characterization of cell types with high sensitivity and coverage. The cumulative data provide the foundation for an atlas of transcriptomic cell biology.

    View details for DOI 10.1038/s41586-018-0590-4

    View details for PubMedID 30283141

  • Bifunctional Anti-Non-Amyloid Component alpha-Synuclein Nanobodies Are Protective In Situ PLOS ONE Butler, D. C., Joshi, S. N., de Genst, E., Baghel, A. S., Dobson, C. M., Messer, A. 2016; 11 (11)

    Abstract

    Misfolding, abnormal accumulation, and secretion of α-Synuclein (α-Syn) are closely associated with synucleinopathies, including Parkinson's disease (PD). VH14 is a human single domain intrabody selected against the non-amyloid component (NAC) hydrophobic interaction region of α-Syn, which is critical for initial aggregation. Using neuronal cell lines, we show that as a bifunctional nanobody fused to a proteasome targeting signal, VH14PEST can counteract heterologous proteostatic effects of mutant α-Syn on mutant huntingtin Exon1 and protect against α-Syn toxicity using propidium iodide or Annexin V readouts. We compared this anti-NAC candidate to NbSyn87, which binds to the C-terminus of α-Syn. NbSyn87PEST degrades α-Syn as well or better than VH14PEST. However, while both candidates reduced toxicity, VH14PEST appears more effective in both proteostatic stress and toxicity assays. These results show that the approach of reducing intracellular monomeric targets with novel antibody engineering technology should allow in vivo modulation of proteostatic pathologies.

    View details for DOI 10.1371/journal.pone.0165964

    View details for Web of Science ID 000387615200051

    View details for PubMedCentralID PMC5100967