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

The most common inherited form of Fronto-Temporal Lobar Degeneration (FTLD) stems from Progranulin (GRN) mutations, and exhibits TDP-43 plus ubiquitin protein aggregates in brain. Although it is well established that disease causing mutations in GRN lead to haploinsufficiency of Progranulin (PGRN), the neurobiology of this secreted glycoprotein is unclear. We examined PGRN binding to the cell surface, and found that PGRN binds to mature cortical neurons with high affinity via its C-terminus. Through an unbiased expression cloning strategy we identified Sortilin (Sort1 ) as a major high affinity binding site. Sort1-/- neurons exhibit reduced PGRN binding, identifying Sortilin as a major cell surface binding site for PGRN. In the CNS, Sortilin is expressed by neurons and PGRN is most strongly secreted by activated microglial cells after neuronal stress. The functional consequence of this paracrine interaction is rapid delivery of PGRN to lysosomes via Sortilin-mediated endocytosis. Mice lacking Sortilin have elevated brain and serum PGRN levels of 2.5- to 5-fold. The ∼50% decrease in PGRN levels causative in FTLD cases with GRN mutations is mimicked in PGRN+/- mice, and is fully corrected by Sort1 ablation. PGRN's natural role may be to support the function of lysosomes in neurons, because loss of PGRN results in lipofuscinosis and accumulation of autolysosomal structures. Our results indicate titration of Sortilin-mediated PGRN endocytosis is likely to play a central role in FTLD pathophysiology.