Project 3

Research Project 3:
The role of AP-5 in the endolysosomal system, autophagy and autophagic lysosome reformation

 

Principal Investigator

Prof. Dr. med. Christian Hübner

Associated PI

Dr. rer. nat. Mukhran Khundadze

PhD Student

Federico Ribaudo

 


 

Project Summary

Mutations in the zeta subunit (SPG48) of the recently identified adaptor protein complex 5 (AP-5) are associated with hereditary spastic paraplegia, a neurodegenerative disorder. AP-5 interacts with two additional proteins associated with hereditary spastic paraplegia, i.e. Spatacsin (SPG11) and Spastizin (SPG15), which are thought to be involved in the recycling of lysosomes from autophagosomes. In the context of the FOR2625 we want to define the roles of these proteins in the degradative pathway using both cellular and in vivo models. This project will include molecular biology, genome editing, cell culture, life cell microscopy and mouse work.

 

What is the role of the AP-5, SPG11, SPG15 complex within the degradataive pathway?The Golgi and the endolysosomal pathway are labeled in blue, autophagy in grey, and ALR in green. Orange dashes: lysosomal enzymes, Black circles: autophagic material. ER: Endoplasmatic Reticulum, C: cargo

 

References

Beetz C, Koch N, Khundadze M, Zimmer G, Nietzsche S, Hertel N, Huebner AK, Mumtaz R, Schweizer M, Dirren E, Karle KN, Irintchev A, Alvarez V, Redies C, Westermann M, Kurth I, Deufel T, Kessels MM, Qualmann B, Hübner CA (2013) A spastic paraplegia mouse model reveals REEP1-dependent ER shaping. J Clin Invest 123:4273-82

Khundadze M, Kollmann K, Koch N, Biskup C, Nietzsche S, Zimmer G, Hennings JC, Huebner AK, Symmank J, Jahic A, Ilina EI, Karle K, Schols L, Kessels M, Braulke T, Qualmann B, Kurth I, Beetz C, Hübner CA (2013) A hereditary spastic paraplegia mouse model supports a role of ZFYVE26/SPASTIZIN for the endolysosomal system. PLoS Genet 9:e1003988

Varga RE, Khundadze M, Damme M, Nietzsche S, Hoffmann B, Stauber T, Koch N, Hennings JC, Franzka P, Huebner AK, Kessels MM, Biskup C, Jentsch TJ, Qualmann B, Braulke T, Kurth I, Beetz C, Hübner CA (2015) In Vivo Evidence for Lysosome Depletion and Impaired Autophagic Clearance in Hereditary Spastic Paraplegia Type SPG11. PLoS Genet 11:e1005454

Hirst J, Barlow LD, Francisco GC, Sahlender DA, Seaman MN, Dacks JB, Robinson MS (2011) The fifth adaptor protein complex. PLoS Biol 9:e1001170

Chang J, Lee S, Blackstone C (2014) Spastic paraplegia proteins spastizin and spatacsin mediate autophagic lysosome reformation. J Clin Invest 124:5249-62