Aarhus Universitet

Christian Bjerggaard Vægter

Sortilin-Mediated Endocytosis Determines Levels of the Fronto-Temporal Dementia Protein, Progranulin

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  • Fenghua Hu, Yale University School of Medicine, USA
  • Thihan Padukkavidana, Yale University School of Medicine, USA
  • Christian Bjerggaard Vægter
  • Owen Brady, Weill Institute for Cell and Molecular Biology, Cornell University, USA
  • Yanqiu Zheng, Weill Institute for Cell and Molecular Biology, Cornell University, Danmark
  • Ian Mackenzie, University of British Columbia, Canada
  • Howard Feldman, Yale University School of Medicine, USA
  • Anders Nykjær
  • Stephen Strittmatter, Yale University School of Medicine, USA
  • Institut for Medicinsk Biokemi

The most common inherited form of Fronto-Temporal Lobar Degeneration (FTLD) known

stems from Progranulin (GRN) mutation, and exhibits TDP-43 plus ubiquitin protein aggregates in

brain. Despite the causative role of GRN haploinsufficiency in FTLD-TDP, the neurobiology of this

secreted glycoprotein is unclear. Here, we examined PGRN binding to the cell surface. PGRN binds to

cortical neurons with high affinity via its C-terminus, and unbiased expression cloning identifies

Sortilin (Sort1) as a binding site. Sort1-/- neurons exhibit reduced PGRN binding. In the CNS, Sortilin

is expressed by neurons and PGRN is most strongly expressed by activated microglial cells after injury.

Sortilin rapidly endocytoses and delivers PGRN to lysosomes. Mice lacking Sortilin have elevations in

brain and serum PGRN levels of 2.5- to 5-fold. The 50% PGRN decrease causative in FTLD-TDP cases is

mimicked in GRN+/- mice, and is fully normalized by Sort1 ablation. Sortilin-mediated PGRN

endocytosis is likely to play a central role in FTLD-TDP pathophysiology

OriginalsprogEngelsk
TidsskriftNeuron
Vol/bind68
Nummer4
Sider (fra-til)654-667
ISSN0896-6273
StatusUdgivet - 2010

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