Determining the role of KIF5A in amyotrophic lateral sclerosis (ALS) pathogenesis

 Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disorder characterized by the loss of upper and lower motor neurons and leads to progressive paralysis and demise of patients in 2-5 years following diagnosis. This adult-onset disease is mostly sporadic in nature (90% of cases) but over the last decades, many causative mutations have been identified in both sporadic and familial ALS patients, uncovering diverse pathogenic mechanisms underlying neurodegeneration. KIF5A has recently been identified as an ALS-linked gene but its role in pathogenesis is still unknown. Interestingly, it encodes a motor protein responsible for the intracellular transport of cargo, a process essential for neuron growth and function which is known to be impaired in many neurodegenerative diseases and across ALS subtypes. I propose to characterize the role of KIF5A in ALS pathogenesis using the embryonic zebrafish model and reconstructed human neuromuscular junctions from induced pluripotent stem cells bearing ALS mutations. These two approaches will allow me to understand how mutations in KIF5A affect its function in the context of motor neuron development and function, both in vitro and in vivo, with a focus on axonal transport. Finally, because previous work from our group has shown that HDAC6 inhibition was sufficient to reverse axonal transport defects in FUS-ALS models, I will evaluate the therapeutic potential of HDAC6 inhibition on our KIF5A-ALS models.
GENERAL