Salasova, A. | Search bioRxiv

bioRxiv2023

SorCS2 binds progranulin and regulates motor axon outgrowth

Motor neuron development requires an orchestrated action of trophic factors and guidance cues for axons to reach their targets. Here, we identify SorCS2 as a novel receptor for progranulin (PGRN) that is required for motor axon outgrowth in zebrafish and mice. In both species motor neurons express SorCS2, and PGRN is produced in cells juxta-positioned the projecting axon, but in mice the neurons also co-express PGRN. In zebrafish, sorcs2 knockdown produces stunted and aberrantly branched motor axons, and in Sorcs2-/- mice, forelimb innervation and motor neuron regeneration are substantially perturbed; phenotypes also observed in fish and mice lacking PGRN. SorCS2 binds PGRN and while motor neuron cultures from wildtype mice respond to exogenous PGRN by axon outgrowth, knockout neurons are unresponsive. Remarkably, when co-expressed in the same cells, SorCS2 controls secretion of PGRN. We conclude that SorCS2 navigates motor neuron development and enables axon regeneration through binding of PGRN.

developmental biology↗

bioRxiv2021

SorCS2 dynamically interacts with TrkB and GluN2B to control neurotransmission and Huntington's disease progression

BackgroundHuntingtons disease (HD) is a fatal neurodegenerative disorder characterized by progressive motor dysfunction and loss of medium spiny neurons (MSNs) in dorsal striatum. Brain-derived neurotrophic factor (BDNF) sustains functionality and integrity of MSNs, and thus reduced BDNF signaling is integral to the disease. Mutations in BDNF receptor SorCS2 were recently identified in HD patients. Our study investigates the role of SorCS2 in MSNs biology and in HD progression. MethodsWe derived a double transgenic line by crossbreeding SorCS2 deficient (KO) mice with the HD mouse model R6/1. Subsequently, we characterized the SorCS2 KO; R6/1 line by a set of behavioral and biochemical studies to evaluate phenotypes related to HD. Moreover, in combination with electrophysiology and super resolution microscopy techniques, we addressed the molecular mechanism by which SorCS2 controls synaptic activity in MSNs neurons. ResultsWe show that SorCS2 is expressed in MSNs with reduced levels in R6/1 HD model, and that SorCS2 deficiency exacerbates the disease progression in R6/1 mice. Furthermore, we find that SorCS2 binds TrkB and the NMDA receptor subunit GluN2B, which is required to control neurotransmission in corticostriatal synapses. While BDNF stimulates SorCS2-TrkB complex formation to enable TrkB signaling, it disengages SorCS2 from GluN2B, leading to enrichment of the subunit at postsynaptic densities. Consequently, long-term potentiation (LTP) is abolished in SorCS2 deficient mice, despite increased striatal TrkB and unaltered BDNF expression. However, the addition of exogenous BDNF rescues the phenotype. Finally, GluN2B, but not GluN2A, currents are also severely impaired in the SorCS2 KO mice. ConclusionsWe formulate a novel molecular mechanism by which SorCS2 acts as a molecular switch. SorCS2 targets TrkB and GluN2B into postsynaptic densities to enable BDNF signaling and NMDAR dependent neurotransmission in the dorsal striatum. Remarkably, the binding between SorCS2 and TrkB or GluN2B, respectively, is mutually exclusive and controlled by BDNF. This mechanism provides an explanation why deficient SorCS2 signaling severely aggravates HD progression in mice. Moreover, we provide evidence that this finding might represent a general mechanism of SorCS2 signaling found in other brain areas, thus increasing its relevance for other neurological and psychiatric impairments.

neuroscience↗