Midtveisevaluering - Ida Ajvazi Herdlevær
Midtveisevaluering for ph.d.-graden ved Universitetet i Bergen for kandidat Ida Ajvazi Herdlevær
Ida Ajvazi Herdlevær er tilknyttet Klinisk institutt 1. Veiledere er Christian Vedeler, Manja Schubert og Sonia Gavasso.
Paraneoplastic cerebellar degeneration: mechanistic insight on CDR protein function to develop neuroprotective treatments
Paraneoplastic cerebellar degeneration (PCD) is a rare autoimmune-mediated neurodegenerative disease that is associated with onconeuronal autoantibodies and subacute cerebellar ataxia. In gynecological cancer, the most frequently detected PCD autoantibody is anti-Yo. Anti-Yo reacts with ovary and breast cancer cells, but can also react with cerebellar Purkinje neurons by crossing the blood-brain barrier. In Purkinje neurons, anti-Yo binds to the cerebellar degeneration-related antigens, CDR2 and CDR2L. This binding causes neuronal dysfunction and Purkinje neuron death, and thereby leads to gradual loss of motor control in PCD patients.
By today, our knowledge in terms of cellular and molecular mechanisms that mediate PCD pathogenesis is limited. Therefore, we want to investigate the cellular location of CDR2 and CDR2L in cancer cell lines and identify protein-protein interaction partners to address the functions of the CDR proteins. Preliminary data indicate that CDR2 is associated with nuclear speckles and cytoplasmic filaments, implying a functional role in signal transduction and/or gene transcription. CDR2L is located in close proximity to membrane-bound organelles, such as the endoplasmic reticulum, suggesting a functional role in regulation of calcium signaling.
Since most antigens of onconeuronal antibodies are intracellular, it has been argued that antibodies to these targets are unlikely to be pathogenic. It has been presumed that the extensive loss of Purkinje neurons observed in PCD patients is mainly caused by T-cell infiltration and microglia activation. In this project, we want to investigate the function and location of microglia in the late phase of PCD in human cerebellum sections, using a new technique called imaging mass cytometry.