CK2-Mediated Dysregulation of Fast Axonal Transport in Hereditary Spastic Paraplegia

The Role of CK2-Mediated Fast Axonal Transport Dysregulation in Hereditary Spastic Paraplegia Matthew Robert Burns, M.D., Ph.D. Department of Anatomy and Cell Biology University of Illinois at Chicago Chicago, Illinois (2014) Dissertation Chairperson: Jonathan Art, Ph.D. HSPs are a genetically diverse group of disorders resulting in degeneration the corticospinal tracts and dorsal column fibers of motor neurons. Patients show progressive muscle weakness and spastic paralysis of the lower limbs and are often confined to a walker or wheelchair. There is currently no medical treatment or known pathogenic mechanism. Mutations in the SPG4 gene are the most common cause of HSP. The SPG4 gene codes for two isoforms of the microtubule-severing protein spastin, called M1 and M87. SPG4-HSP patients develop "dying back" motor neuron pathology where synapses and axons degenerate prior to death of the cell body. Significantly, this type of pathology has been associated with deficits in fast axonal transport. Despite this evidence, the mechanisms underlying axonal transport deficits in SPG4-HSP remain unknown. Recently published work and these data show that 1) M1 spastin is predominantly expressed in the adult spinal cord, the precise age and location of axonal degeneration in HSP; 2) mutant M1 spastin isoform, but not mutant M87, inhibit fast axonal transport (FAT), suggesting a mechanism involving the N-terminus unique to the M1 isoform; 3) transport inhibition can be blocked by a specific pharmacological inhibitor or phosphorylation substrate of the serine/threonine kinase CK2, suggesting that CK2 mediates this transport inhibition; and 4.) expression of the mutant M1 spastin isoform in a human cell line increases CK2 kinase activity relative to mutant M87 spastin isoform. This data suggest a working model in which mutations in spastin induce an M1 isoform-specific region to activate CK2, altering kinesin activity through its phosphorylation.