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.

Zebrafish GDNF and its co-receptor GFRα1 activate the human RET receptor and promote the survival of dopaminergic neurons in vitro

“…This is most likely due to the sequence divergence and presumable structural divergence seen from the poorly conserved sequence identity (Tables 2 and 3) and from the alignments (Fig 8). There might not be a conserved RET/GFRα/GDNF signaling system in fruit fly and perhaps dRET might be constitutively held inactive by dGFRLs, as a part of a sorting receptor protein complex as has been suggested for other GFRα molecules [38]. These results question the role of dRET with a functional active tyrosine kinase domain as shown by Abrescia et al .…”

Sorting receptor SORLA: cellular mechanisms and implications for disease

“…SORLA interacts with GDNF to increase its regulated secretion from cells [47]. In addition, SORLA interacts with GFRα1, the co-receptor for GDNF [48]. SORLA facilitates internalization of GFRα1/GDNF complexes from the plasma membrane, resulting in lysosomal catabolism of GDNF but cell surface recycling of GFRα1.…”

“…SORLA facilitates internalization of GFRα1/GDNF complexes from the plasma membrane, resulting in lysosomal catabolism of GDNF but cell surface recycling of GFRα1. This sorting route provides an efficient pathway for clearance of GDNF from the extracellular space and counteracts consequences of excessive GDNF signaling, such as hyperactivity and reduced anxiety (as seen in mice lacking SORLA) [48]. Finally, SORLA also impacts signaling through a heterodimeric neurotrophic cytokine called cardiotrophin-like cytokine:cytokine-like factor 1 (CLC:CLF-1) [49].…”

Late-Onset Alzheimer’s Disease Genes and the Potentially Implicated Pathways

“…Additionally, single-site and haplotype association of SORL1 with risk of amnestic mild cognitive impairment (aMCI), a common precursor to AD, has been reported in the Han Chinese [88]. Glerup et al [89] have demonstrated SORL1 as an endocytic modulator of glial-derived neurotrophic factor (GDNF) and its related receptor, GFRα1.…”