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

被引：415

作者：

Hu, Fenghua ^{[1
,2
,3
,4
]}

Padukkavidana, Thihan ^{[1
,2
,3
]}

Vaegter, Christian B. ^{[5
]}

Brady, Owen A. ^{[4
]}

Zheng, Yanqiu ^{[4
]}

Mackenzie, Ian R. ^{[6
]}

Feldman, Howard H. ^{[1
,2
,3
,7
]}

Nykjaer, Anders ^{[5
]}

Strittmatter, Stephen M. ^{[1
,2
,3
]}

机构：

[1] Yale Univ, Sch Med, Dept Neurol, New Haven, CT 06536 USA

[2] Yale Univ, Sch Med, Dept Neurobiol, New Haven, CT 06536 USA

[3] Yale Univ, Sch Med, Program Cellular Neurosci Neurodegenerat & Repair, New Haven, CT 06536 USA

[4] Cornell Univ, Dept Mol Biol & Genet, Weill Inst Cell & Mol Biol, Ithaca, NY 14853 USA

[5] Aarhus Univ, Dept Med Biochem, Lundbeck Fdn Res Ctr MIND, DK-8000 Aarhus C, Denmark

[6] Univ British Columbia, Dept Pathol, Vancouver, BC V5Z 1M9, Canada

[7] Bristol Myers Squibb, Global Clin Res, Dept Neurosci, Wallingford, CT 06492 USA

来源：

NEURON | 2010年 / 68卷 / 04期

基金：

美国国家卫生研究院;

关键词：

LOBAR DEGENERATION; LYSOSOMAL TRAFFICKING; HOST-DEFENSE; RECEPTOR; MUTATIONS; TDP-43; MICE; NEUROPATHOLOGY; DISRUPTION; PROTEASOME;

D O I：

10.1016/j.neuron.2010.09.034

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

The most common inherited form of Frontotemporal Lobar Degeneration (FTLD) known stems from Progranulin (GRN) mutation and exhibits TDP-43 plus ubiquitin aggregates. 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 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.

引用

页码：654 / 667

页数：14

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