Jens Randel Nyengaard

SorLA Controls Neurotrophic Activity by Sorting of GDNF and Its Receptors GFRα1 and RET

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SorLA Controls Neurotrophic Activity by Sorting of GDNF and Its Receptors GFRα1 and RET. / Glerup, Simon; Lume, Maria; Olsen, Ditte; Nyengaard, Jens R; Vaegter, Christian B; Gustafsen, Camilla; Christensen, Erik I; Kjolby, Mads; Hay-Schmidt, Anders; Bender, Dirk; Madsen, Peder; Saarma, Mart; Nykjaer, Anders; Petersen, Claus M.

In: Cell Reports, Vol. 3, 16.01.2013, p. 186-199.

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@article{961e6f8099384a5db031cf94e5960127,
title = "SorLA Controls Neurotrophic Activity by Sorting of GDNF and Its Receptors GFRα1 and RET",
abstract = "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.",
author = "Simon Glerup and Maria Lume and Ditte Olsen and Nyengaard, {Jens R} and Vaegter, {Christian B} and Camilla Gustafsen and Christensen, {Erik I} and Mads Kjolby and Anders Hay-Schmidt and Dirk Bender and Peder Madsen and Mart Saarma and Anders Nykjaer and Petersen, {Claus M}",
note = "Copyright {\textcopyright} 2013 The Authors. Published by Elsevier Inc. All rights reserved.",
year = "2013",
month = jan,
day = "16",
doi = "10.1016/j.celrep.2012.12.011",
language = "English",
volume = "3",
pages = "186--199",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",

}

RIS

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 R

AU - Vaegter, Christian B

AU - Gustafsen, Camilla

AU - Christensen, Erik I

AU - Kjolby, Mads

AU - Hay-Schmidt, Anders

AU - Bender, Dirk

AU - Madsen, Peder

AU - Saarma, Mart

AU - Nykjaer, Anders

AU - Petersen, Claus M

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

PY - 2013/1/16

Y1 - 2013/1/16

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.

U2 - 10.1016/j.celrep.2012.12.011

DO - 10.1016/j.celrep.2012.12.011

M3 - Journal article

C2 - 23333276

VL - 3

SP - 186

EP - 199

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

ER -