Hutchinson-Gilford Progeria Syndrome (HGPS, OMIM #177670) is a rare genetic disorder characterized by mutations in the nuclear protein lamin A. Mutations result in premature aging (progeria), severe cardiovascular complications and early death. A full understanding of HGPS is not yet available and therapeutic strategies are far from being optimized. It is established that HGPS mutations cause nuclear fragility and telomeric defects. However, the understanding of the interplay between telomeric defects and nuclear fragility is in its infancy. Along with this, the implication of the ESCRT (endosomal sorting complexes required for transport) machinery, which controls nuclear fragility, is yet unexplored in HGPS and other telomeric disorders, and also in telomere biology. We have experimental evidence that a factor named AKTIP controls telomere biology, is enriched at the nuclear border interacting with lamin A, is associated with ESCRTs and affected by HGPS mutations. In this project I want to build on the link between the nuclear border, ESCRTs and telomeres, highlighted by AKTIP, with the aims of deepening the understanding of the interaction between AKTIP, ESCRTs and telomeres, assessing the relationships between ESCRTs and telomeres in HGPS and explore new paths for therapy of HGPS, by evaluating the ESCRT complex as a therapeutic tool. To achieve these aims I will characterize by super resolution microscopy and biochemistry nuclear border, telomeres and ESCRTs in wild type and HGPS conditions. I will screen for ESCRT mutations patient samples with progeroid phenotype and produce vectors encoding ESCRT components as gene therapy approach to rescue HGPS nuclear fragility.
HGPS is rare gentic diseases caused by mutations in LMNA gene characterized by premature aging (progeria), severe cardiovascular complications and early death. From a therapeutic point of view encouraging results were obtained by combined use of drugs impinging on progerin production or accumulation and /or on molecular pathway activated in patients cells; however no treatment has proven fully successful, which suggests that further understanding of the disease is needed to design more innovative and successful therapeutic strategies for HGPS. It is established that HGPS mutations cause nuclear fragility and telomeric defects but the understanding of the interplay between telomeric defects and nuclear fragility is far to be clear. Along with this it¿s know that ESCRTs are associated with nuclear fragility and telomeres, the dissection of the relationships are poorly defined. I plan to fill this gap and I¿m confident that this study can help in providing insights on mechanisms of action of ESCRTs in HGPS and telomeric defects and of their translational potential for HGPS and other telomeric disorders.
References of the project:
1. Hennekam, R.C., Hutchinson-Gilford progeria syndrome: review of the phenotype. Am J Med Genet A, 2006. 140(23): p. 2603
2. De Sandre-Giovannoli, A., et al., Lamin a truncation in Hutchinson-Gilford progeria. Science, 2003. 300(5628)
3. Verstraeten, V.L., et al., Increased mechanosensitivity and nuclear stiffness in Hutchinson-Gilford progeria cells: effects of farnesyltransferase inhibitors. Aging Cell, 2008. 7(3)
4. Rodier, F., J. Campisi, Four faces of cellular senescence. J Cell Biol, 2011. 192(4)
5. Gordon, L.B., et al., Clinical Trial of the Protein Farnesylation Inhibitors Lonafarnib, Pravastatin, and Zoledronic Acid in Children With Hutchinson-Gilford Progeria Syndrome. Circulation, 2016. 134(2
6. Cenni, V., et al., Autophagic degradation of farnesylated prelamin A as a therapeutic approach to lamin-linked progeria. Eur J Histochem, 2011. 55(4)
7. Gonzalo, S., R. Kreienkamp, and P. Askjaer, Hutchinson-Gilford Progeria Syndrome: A premature aging disease caused by LMNA gene mutations. Ageing Res Rev, 2017.33
8. Pellegrini, C., et al., All-trans retinoic acid and rapamycin normalize Hutchinson Gilford progeria fibroblast phenotype. Oncotarget, 2015. 6(30)
9. Larrieu, D., et al., Chemical inhibition of NAT10 corrects defects of laminopathic cells. Science, 2014. 344(6183)
10. Balmus, G., et al., Targeting of NAT10 enhances healthspan in a mouse model of human accelerated aging syndrome. Nat Commun, 2018. 9(1)
11. Harhouri, K., et al., Antisense-Based Progerin Downregulation in HGPS-Like Patients' Cells. Cells, 2016. 5
12. Schmidt, O. and D. Teis, The ESCRT machinery. Curr Biol, 2012. 22(4)
13. Christ, L., et al., ALIX and ESCRT-I/II function as parallel ESCRT-III recruiters in cytokinetic abscission. J Cell Biol, 2016. 212(5)
14. Crabbe, L., et al., Human telomeres are tethered to the nuclear envelope during postmitotic nuclear assembly. Cell Rep, 2012. 2(6)
15.Burla, R., et al., Interplay of the nuclear envelope with chromatin in physiology and pathology. Nucleus, 2020. 11(1)
16.Olmos, Y. and J.G. Carlton, The ESCRT machinery: new roles at new holes. Curr Opin Cell Biol, 2016. 38
17.Raab, M., et al., ESCRT III repairs nuclear envelope ruptures during cell migration to limit DNA damage and cell death. Science, 2016. 352(6283)
18.Denais, C.M., et al., Nuclear envelope rupture and repair during cancer cell migration. Science, 2016. 352(6283)
19.Robijns, J., et al., In silico synchronization reveals regulators of nuclear ruptures in lamin A/C deficient model cells. Sci Rep, 2016. 6
20.Burla, R., et al., AKTIP/Ft1, a New Shelterin-Interacting Factor Required for Telomere Maintenance. PLoS Genet, 2015. 11(6)
21.Burla, R., et al., The telomeric protein AKTIP interacts with A- and B-type lamins and is involved in regulation of cellular senescence. Open Biol, 2016. 6(8)
22.Olmos, Y., et al., ESCRT-III controls nuclear envelope reformation. Nature, 2015. 522(7555).
23.Cenci, G., et al., The Analysis of Pendolino (peo) Mutants Reveals Differences in the Fusigenic Potential among Drosophila Telomeres. PLoS Genet, 2015. 11(6)
24.Burla, R., M. La Torre, and I. Saggio, Mammalian telomeres and their partnership with lamins. Nucleus, 2016. 7(2)
25.Vietri, M., et al., Spastin and ESCRT-III coordinate mitotic spindle disassembly and nuclear envelope sealing. Nature, 2015. 522(7555)
26.La Torre, M., et al., Mice with reduced expression of the telomere-associated protein Ft1 develop p53-sensitive progeroid traits. Aging Cell, 2018
27.Osorio, F.G., et al., Splicing-directed therapy in a new mouse model of human accelerated aging. Sci Transl Med, 2011. 3(106)
28.Hanson, L., et al., Vertical nanopillars for in situ probing of nuclear mechanics in adherent cells. Nat Nanotechnol, 2015. 10(6)