Scott Brady, PhD

Dr. Scott Brady (Anatomy and Cell Biology)

Dr. Jeff Loeb (Neurology and Rehabilitation)

Frontotemporal dementia (FTD) is a neurodegenerative disease that primarily affects the frontal and temporal lobes of the brain, resulting in behavior and personality changes. The hexanucleotide repeat expansion in the chromosome 9 open reading frame 72 (C9ORF72) gene has been identified as the most common genetic cause of FTD. One proposed mechanism that implicates the G4C2 repeats in the initiation of neurodegenerative changes is a gain of function due to the formation and accumulation of dipeptide repeat proteins through repeat-associated non-AUG (RAN) translation of the hexanucleotide repeat sequences from both sense and antisense strands. Numerous mechanistic questions about C9orf72-related neurodegeneration remain unanswered. Preliminary studies from our lab have suggested that there is an impairment of anterograde fast axonal transport as well as axonal degeneration occurring in neurons expressing the poly-GP dipeptide. These studies have also indicated

that these axon-specific effects work through the activation of a P38𝛼 MAPK signaling pathway.

Additionally, Aurora B is a serine/threonine kinase that has previously been suggested in the literature to help regulate axonal outgrowth and regeneration in spinal motor neurons. Primary cortical neurons treated with an Aurora B kinase inhibitor displayed shorter neurites likely to become dendrites or axons, suggesting a potential role for the kinase in non-dividing cells. Our hypothesis is that Aurora B kinase influences the development of C9orf72-specific toxic effects, whether it occurs through a change in protein levels and/or the activation of downstream signaling pathways.