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Stephen Tymanskyj, PhD

Assistant Professor, Neuroscience

Research Summary

The nervous system is a collection of highly specialized cells that wire together to form highly complexed circuits which underlie everything that we do. The key component of this system is the neuron. Composed of dendrites which receive signal at the cell body, and axons that extends away to from contacts or synapses with other cells. These synapses allow for transmission of signals between the presynapse and the postynapase, underlying all the functions of the nervous system. The dendrites, although small, are very important, with their arbors covering a restricted region. In contrast the axon projection are often vast. Not only long, it is responsible for projecting to multiple compartments of the brain. Additionally stepping away from the brain, peripheral projecting neurons such as motor neurons and sensory neurons have to cover huge distances, up to a meter in humans. As the distance and complexity are critical for function, understanding how these projections are generated and maintained is highly important.

Axons are often highly branched and interact with their environment to be either stabilized or pruned away, establishing the correct circuitry. For this to happen, proteins are constantly being moved around the axon, from sites where they are not needed to those where they are. In many instances proteins are generated in the cell body, where they are packaged into vesicles and transported throughout the neuron, where they can move both forward and backwards depending. For cargo movement to occur they need tracks to move along. In cells and neurons this comes in the from of microtubules which have important roles in providing neuronal structure but can be heavily modified to help regulate cargo transport. Much like a freeway, where cars are the cargo and the microtubules the individual lanes, this system, much like a freeway allow cargos to switch lanes or tracks to maintain highly processive movements and overcome obstacles or jams.

The importance of regulated transport is demonstrated by the number of diseases, both neurodevelopmental and degenerative that are affected by defects in axon transport. The occur through a direct effect on the motor itself such as in ALS which leads to truncated, hyperactive form of kinesin. Similarly, there are a whole number of diseases associated with mutations of the KIF1A termed KANDS. Further, there are indirect mechanisms which impact transport, where mutant forms of non motor proteins impact the efficiency of the motor. This includes examples such as in Parkinsons, where hyperactive LRRK2 leads to an increase in kinesin activity and also in Alzheimer's, where protein misregulation can alter the microtubule tracks themselves, but also influence the binding of the motor to the cargo. Understanding how these motor and the cargos are regulated is important for any potential therapeutic intervention.