CK2-mediated reduction in Fast Axonal Transport by a cytoplasmic form of Prion Protein

ZAMPONI E; BURATTI F; HELGUERA P; PIGINO G

Mar del Plata

Congreso; XXX annual meeting Sociedad Argentina de Investigación en Neurociencias (SAN); 2015

Sociedad Argentina de Investigación en Neurociencias (SAN)

Prion diseases (PrD) are fatal progressive neuropathies characterized by specific neuronaland synaptic dysfunction and loss, associated accumulation of pathogenic forms of PrionProtein (PrP). Loss of synaptic connectivity occurs early in PrD. Several studies point to aspecific domain in the PrP sequence as the major trigger of the disease features. However,neither the exact segment of the PrP involved nor the pathological mechanism of its actionhas been described. Reductions in fast axonal transport (FAT) has been associated withdying back neuropathies and mutations in functional domains of kinesins or dyneins lead toneurodegeneration. Nontheless, mutations in motor proteins have not been described inPrD. An alternative explanation is that alterations in FAT regulatory pathways result in areduce delivery of critical synaptic components, leading to failure of synapses and loss ofneurons following a dying back pattern. Here we evaluated the effects of the PrP 106-126peptide domain on kinesin-1 and dynein-based FAT. Ex-vivo and biochemical experimentsreveal that abnormal casein kinase 2 (CK2) activation mediates PrP induced inhibition ofboth anterograde and retrograde FAT. Significantly, PrP-mediated FAT inhibition can beprevented by a specific CK2 inhibitor. In summary, our results suggest reduction of FATinduced by an imbalance in specific kinase activities in neurons by PrP may represent anearly, critical step for initiation of neuronal pathology.