CDR2 and CDR2L

To develop neuroprotective therapy for PCD patient we have to identify the molecular mechanisms and signaling pathways that are affected after onconeuronal auto-antibody Yo (anti-Yo) pass the blood-brain barrier and bind to cerebellar degeneration-related protein CDR2 and/or CDR2L in Purkinje neurons. To achieve these detailed insights we have to answer some essential questions:

First: What are the functions of both anti-Yo targeted proteins CDR2 and CDR2L in Purkinje neurons?

Very little is known! From a few neurological as well as cancer studies we are confident that CDR2 interacts with calbindin D28K (calcium buffer/modulator); protein kinase N1 (PKN1, signal transduction) and c-myc (nuclear phosphorprotein; cellular transformation), all proteins important for cell survival. Yet, the function/interaction of CDR2L is still undiscovered.

Second: Which biochemical processes are dysregulated when anti-Yo incorporates and binds to CDR2 and/or CDR2L proteins in Purkinje neurons?

To unravel that complexity we have developed different ex-vivo PCD models in the last five years. We discovered that anti-Yo incorporation and binding leads to cellular calcium overload and mitochondrial dysfunction. The activity/function of voltage-gated calcium channels (VGCC), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR), sodium/calcium channels (NCX), mitochondria permeability transition pore (MPTP), protein kinase C gamma (PKCγ), calbindin D28K and calpain-2 was heavily altered dependent on whether CDR2 or CDR2L was the anti-Yo target (DOI: 10.1007/s00401-014-1351-6 + 10.1111/nan.12492).