Poul Henning Jensen

Tubulin Polymerization Promoting Protein (TPPP/p25α) promotes unconventional secretion of α-synuclein through exophagy by impairing autophagosome-lysosome fusion

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  • Patrick Ejlerskov, University of Copenhagen, Denmark
  • Izabela Zorawska Rasmussen, University of Copenhagen, Denmark
  • Troels Tolstrup Nielsen, University of Copenhagen, Denmark
  • Ann-Louise Bergström
  • ,
  • Yumi Tohyama
  • ,
  • Poul Henning Jensen
  • Frederik Vilhardt, University of Copenhagen, Denmark
Aggregation of α-synuclein can be promoted by the tubulin polymerization-promoting protein (TPPP)/p25α, which we have here used as a tool in order to study the role of autophagy in the clearance of α-synuclein. In NGF-differentiated PC12 catecholaminergic nerve cells, we show that de novo expressed p25α co-localizes with α-synuclein, and causes its aggregation and distribution into autophagosomes. However, p25α also lowered mobility of autophagosomes and hindered final maturation of autophagosomes by preventing their fusion with lysosomes for final degradation of α-synuclein. Instead, p25α caused a four-fold increase in the basal level of α-synuclein secreted into the medium. Secretion was strictly dependent on autophagy and could be up- (trehalose, Rab1A) or down-regulated (3-MA, ATG5 shRNA) by enhancers or inhibitors of autophagy, or by modulating minus end- (HDAC6 shRNA) or plus end-directed (Rab8) trafficking of autophagosomes along microtubules. Finally, we show in the absence of TPPP/p25α, that α-synuclein release was modulated by dominant mutants of Rab27A, known to regulate exocytosis of late endosomal (and amphisomal) elements, and that both lysosomal fusion block and secretion of α-synuclein could be replicated by knock-down of the p25α target, HDAC6, the predominant cytosolic deacetylase in neurons. Our data indicate that unconventional secretion of α-synuclein can be mediated through exophagy, and that factors, which increase the pool of autophagosomes/amphisomes (e.g. lysosomal disturbance), or alter the polarity of vesicular transport of autophagosomes on microtubules, can result in an increased release of α-synuclein monomer and aggregates to the surroundings.
Original languageEnglish
JournalJournal of Biological Chemistry
Publication statusPublished - 29 Apr 2013

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