Understanding and developing treatment strategies for kinesin-associated neurological diseases

The kinesin KIF1C is a long-distance transporter responsible for the transport of recycling endosomes, secretory vesicles and mRNAs. Mutations in KIF1C result in complex forms of hereditary spastic paraplegia primarily due to length-dependent degeneration of motor neurons. The disease onset is during childhood and is characterised by progressive lower limb spasticity, tremors and cerebellar dysfunction.

My research group has demonstrated that KIF1C undergoes autoinhibitory intramolecular interactions that keep the motor off microtubules unless activated by a cargo. We have demonstrated that interfering with autoinhibition can boost intracellular transport in neurons. We now aim to start a drug discovery programme to identify small molecules that can activate kinesins and might offer a treatment for patients with neurological diseases caused by intracellular transport defects such as KIF1C-associated HSP.

The aims of the PhD project are to verify the treatment strategy in iPSC-derived neuron modelling the disease, develop robust chemical biology assays to screen for small molecules that can boost kinesin-mediated transport and verify these in the preclinical model.