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

Simon Glerup; Maria Lume; Ditte Olsen; Jens Randel Nyengaard; Christian B Vaegter; Camilla Gustafsen; Erik I Christensen; Mads Kjolby; Anders Hay-Schmidt; Dirk Bender; Søren Peder Madsen; Mart Saarma; Anders Nykjaer; Claus Munck Petersen

doi:10.1016/j.celrep.2012.12.011

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

Simon Glerup, Maria Lume, Ditte Olsen, Jens Randel Nyengaard, Christian B Vaegter, Camilla Gustafsen, Erik I Christensen, Mads Kjolby, Anders Hay-Schmidt, Dirk Bender, Søren Peder Madsen, Mart Saarma, Anders Nykjaer, Claus Munck Petersen

30 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Cell Reports
Vol/bind	3
Udgave nummer	1
Sider (fra-til)	186-99
Antal sider	14
DOI	https://doi.org/10.1016/j.celrep.2012.12.011
Status	Udgivet - 31 jan. 2013

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10.1016/j.celrep.2012.12.011

Citationsformater

Glerup, S., Lume, M., Olsen, D., Nyengaard, J. R., Vaegter, C. B., Gustafsen, C., Christensen, E. I., Kjolby, M., Hay-Schmidt, A., Bender, D., Madsen, S. P., Saarma, M., Nykjaer, A., & Petersen, C. M. (2013). SorLA controls neurotrophic activity by sorting of GDNF and its receptors GFRα1 and RET. Cell Reports, 3(1), 186-99. https://doi.org/10.1016/j.celrep.2012.12.011

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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.",

keywords = "Animals, Anxiety, Behavior, Animal, Cell Membrane, Cell Survival, Dopaminergic Neurons, Endocytosis, Glial Cell Line-Derived Neurotrophic Factor, Glial Cell Line-Derived Neurotrophic Factor Receptors, HEK293 Cells, Humans, Lysosomes, Membrane Transport Proteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Multiprotein Complexes, Protein Binding, Protein Transport, Proto-Oncogene Proteins c-ret, Receptors, LDL",

author = "Simon Glerup and Maria Lume and Ditte Olsen and Nyengaard, {Jens Randel} and Vaegter, {Christian B} and Camilla Gustafsen and Christensen, {Erik I} and Mads Kjolby and Anders Hay-Schmidt and Dirk Bender and Madsen, {S{\o}ren Peder} and Mart Saarma and Anders Nykjaer and Petersen, {Claus Munck}",

year = "2013",

month = jan,

day = "31",

doi = "10.1016/j.celrep.2012.12.011",

language = "English",

volume = "3",

pages = "186--99",

journal = "Cell Reports",

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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

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 - 2639-1856

VL - 3

SP - 186

EP - 199

JO - Cell Reports

JF - Cell Reports

IS - 1

ER -

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

Abstract

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