SorLA controls neurotrophic activity by sorting of GDNF and its receptors GFRα1 and RET

TY - JOUR

T1 - SorLA controls neurotrophic activity by sorting of GDNF and its receptors GFRα1 and RET

AU - Glerup, Simon

AU - Lume, Maria

AU - Olsen, Ditte

AU - Nyengaard, Jens Randel

AU - Vaegter, Christian B

AU - Gustafsen, Camilla

AU - Christensen, Erik I

AU - Kjolby, Mads

AU - Hay-Schmidt, Anders

AU - Bender, Dirk

AU - Madsen, Søren Peder

AU - Saarma, Mart

AU - Nykjaer, Anders

AU - Petersen, Claus Munck

N1 - Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

PY - 2013/1/31

Y1 - 2013/1/31

N2 - Glial cell-line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor that has reached clinical trials for Parkinson's disease. GDNF binds to its coreceptor GFRα1 and signals through the transmembrane receptor tyrosine kinase RET, or RET independently through NCAM or syndecan-3. Whereas the GDNF signaling cascades are well described, cellular turnover and trafficking of GDNF and its receptors remain poorly characterized. Here, we find that SorLA acts as sorting receptor for the GDNF/GFRα1 complex, directing it from the cell surface to endosomes. Through this mechanism, GDNF is targeted to lysosomes and degraded while GFRα1 recycles, creating an efficient GDNF clearance pathway. The SorLA/GFRα1 complex further targets RET for endocytosis but not for degradation, affecting GDNF-induced neurotrophic activities. SorLA-deficient mice display elevated GDNF levels, altered dopaminergic function, marked hyperactivity, and reduced anxiety, all of which are phenotypes related to abnormal GDNF activity. Taken together, these findings establish SorLA as a critical regulator of GDNF activity in the CNS.

AB - Glial cell-line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor that has reached clinical trials for Parkinson's disease. GDNF binds to its coreceptor GFRα1 and signals through the transmembrane receptor tyrosine kinase RET, or RET independently through NCAM or syndecan-3. Whereas the GDNF signaling cascades are well described, cellular turnover and trafficking of GDNF and its receptors remain poorly characterized. Here, we find that SorLA acts as sorting receptor for the GDNF/GFRα1 complex, directing it from the cell surface to endosomes. Through this mechanism, GDNF is targeted to lysosomes and degraded while GFRα1 recycles, creating an efficient GDNF clearance pathway. The SorLA/GFRα1 complex further targets RET for endocytosis but not for degradation, affecting GDNF-induced neurotrophic activities. SorLA-deficient mice display elevated GDNF levels, altered dopaminergic function, marked hyperactivity, and reduced anxiety, all of which are phenotypes related to abnormal GDNF activity. Taken together, these findings establish SorLA as a critical regulator of GDNF activity in the CNS.

KW - Animals

KW - Anxiety

KW - Behavior, Animal

KW - Cell Membrane

KW - Cell Survival

KW - Dopaminergic Neurons

KW - Endocytosis

KW - Glial Cell Line-Derived Neurotrophic Factor

KW - Glial Cell Line-Derived Neurotrophic Factor Receptors

KW - HEK293 Cells

KW - Humans

KW - Lysosomes

KW - Membrane Transport Proteins

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Multiprotein Complexes

KW - Protein Binding

KW - Protein Transport

KW - Proto-Oncogene Proteins c-ret

KW - Receptors, LDL

U2 - 10.1016/j.celrep.2012.12.011

DO - 10.1016/j.celrep.2012.12.011

M3 - Journal article

C2 - 23333276

SN - 2211-1247

VL - 3

SP - 186

EP - 199

JO - Cell Reports

JF - Cell Reports

IS - 1

ER -