Cdc42 Inhibition in G93A-hSOD1 Amyotrophic Lateral Sclerosis: In Vitro and In Vivo Studies
Amyotrophic lateral sclerosis (ALS) is a highly progressive neurodegenerative disease affecting motor neurons (MNs) in the motor cortex, brain stem, and spinal cord. Patients ultimately succumb to muscle paralysis by mechanisms of MN axonal retraction, denervation from neuro-muscular junctions (NMJs), and neuronal apoptosis. Previous research has demonstrated that Rho family GTPases, Rac and Rho, are involved in mechanisms of neurite extension, retraction and cell survival, however it remains to be investigated whether Rho GTPase actin-cytoskeleton modulator, Cdc42, plays a role in ALS disease progression. In studying G93A-SOD1 NSC-34 motor neuronal cells treated with Cdc42 inhibitor, ZCL367, we identified that Cdc42 activation in disease-state neurons may be deleterious. Additionally, Cdc42 inhibitors, ZCL367 and high-dose ZCL279, appear to be neuroprotective against the selective degeneration of α-MNs in the ventral horn of G93A-hSOD1 transgenic (Tg) mice.