Cellular Form of Prion Protein Inhibits Reelin-Mediated Shedding of Caspr from the Neuronal Cell Surface to Potentiate Caspr-Mediated Inhibition of Neurite Outgrowth

Abstract

Extension of axonal and dendritic processes in the CNS is tightly regulated by outgrowth-promoting and -inhibitory cues to assure precision of synaptic connections. We identify a novel role for contactin-associated protein (Caspr) as an inhibitory cue that reduces neurite outgrowth from CNS neurons. We show that proteolysis of Caspr at the cell surface is regulated by the cellular form of prion protein (PrP), which directly binds to Caspr. PrP inhibits Reelin-mediated shedding of Caspr from the cell surface, thereby increasing surface levels of Caspr and potentiating the inhibitory effect of Caspr on neurite outgrowth. PrP deficiency results in reduced levels of Caspr at the cell surface, enhanced neurite outgrowth in vitro, and more efficient regeneration of axons in vivo following spinal cord injury. Thus, we reveal a previously unrecognized role for Caspr and PrP in inhibitory modulation of neurite outgrowth in CNS neurons, which is counterbalanced by the proteolytic activity of Reelin.

Identification of Novel γ-Secretase-associated Proteins in Detergent-resistant Membranes from Brain

“…Experiments in mice lacking Caspr showed that it is required in the formation of paranodal junctions that are important for saltatory conduction (63). Caspr is newly reported to be involved in inhibition of neurite outgrowth in CNS neurons (64). Regarding the potential association of Caspr to AD, the CSF and plasma levels of CNTNAP1 and/or CNTN (CNTN1 and/or -2) are altered in AD individuals, and it is possible that these changes could be used for diagnosis of AD (65)(66)(67)(68).…”

Lipid Raft-dependent Endocytosis of Close Homolog of Adhesion Molecule L1 (CHL1) Promotes Neuritogenesis

“…The cells were washed twice with ice-cold PBS. Surface proteins were then biotinylated with 0.5 mg/ml of EZ-Link Sulfo-NHS-LC-Biotin (Pierce) applied for 30 min at 4°C (20). The reactions were stopped by adding 50 mM glycine for 10 min at 4°C.…”

Delayed Applications of L1 and Chondroitinase ABC Promote Recovery after Spinal Cord Injury

“…Open-field locomotion was assessed by a mouse rating scale, the Basso Mouse Scale (BMS; Basso et al, 2006). In addition, motor performance was examined using videobased single-frame motion analysis, an established approach for the evaluation of motor recovery after spinal cord lesions in mice (Apostolova et al, 2006;Chen et al, 2007Chen et al, ,2010Cui et al, 2011;Devanathan et al, 2010;Jakovcevski et al, 2007;Lee et al, 2009;Mehanna et al, 2010;Semler et al, 2011;Xu et al, 2011). Motor behavior of individual animals was recorded while the mice were performing two tasks: the beamwalking test and the pencil-grabbing test.…”