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.
authors: MIND Centre, Department of Biomedicine, Aarhus University, DK-8000 Aarhus C, Denmark. sg@biokemi.au.dk
authors: Simon
authors: S
authors: Glerup
authors: Maria
authors: M
authors: Lume
authors: Ditte
authors: D
authors: Olsen
authors: Jens R
authors: JR
authors: Nyengaard
authors: Christian B
authors: CB
authors: Vaegter
authors: Camilla
authors: C
authors: Gustafsen
authors: Erik I
authors: EI
authors: Christensen
authors: Mads
authors: M
authors: Kjolby
authors: Anders
authors: A
authors: Hay-Schmidt
authors: Dirk
authors: D
authors: Bender
authors: Peder
authors: P
authors: Madsen
authors: Mart
authors: M
authors: Saarma
authors: Anders
authors: A
authors: Nykjaer
authors: Claus M
authors: CM
authors: Petersen
mesh_terms: D000818:Animals; D001007:Anxiety / Q000378:metabolism / Q000473:pathology; D001522:Behavior, Animal; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival; D059290:Dopaminergic Neurons / Q000166:cytology / Q000378:metabolism; D004705:Endocytosis; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism*; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D051096:Proto-Oncogene Proteins c-ret / Q000378:metabolism*; D011973:Receptors, LDL / Q000172:deficiency / Q000378:metabolism*
chemical_list: C494988:Gfra1 protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D026901:Membrane Transport Proteins; D046912:Multiprotein Complexes; D011973:Receptors, LDL; C491168:Sorl1 protein, mouse; D051096:Proto-Oncogene Proteins c-ret