LRRK2-mediated Axonal Dysfunction

Objective/Rationale: 
The Parkinson’s disease-linked Leucine Rich Repeat Kinase 2 (LRRK2) gene causes changes in the length of processes extending from nerve cells especially the axons. Because changes in process outgrowth can be associated with changes in the transport of organelles, nutrients, and/or the tracks responsible for movement, we plan to test the hypothesis that LRRK2 mutations lead to altered axon transport and hence disruption of nerve cell function
Project Description:
Genetic factors associated with Parkinson’s disease may affect fundamental mechanisms underlying the way in which a neuron sends biological materials up and down an axon. This may compromise the ability of neurons to communicate with each other, lead to the accumulation of proteins and organelles, and ultimately cause the axon and subsequently the neuron to degenerate. To test the hypothesis that LRRK2 mutations lead to altered axon transport and disruption of nerve cell function, optical, molecular and cellular techniques will be used to determine changes in the transport of cytoskeletal proteins, mitochondria and neurotransmitter-containing vesicles in dopaminergic axons. Taken together, the proposed studies will determine whether LRRK2-induced axonal injury plays a central role in the death of dopaminergic neurons.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
An emerging idea in Parkinson’s disease is that axonal transport dysfunction may play an early, pivotal role. New information identifying and characterizing how axonal injury occurs in Parkinson’s disease has enormous potential for the discovery of novel therapies that can be targeted to the elucidated control points in order to stop or slow disease progression.
Anticipated Outcome:
The proposed studies will determine whether genetically induced axonal injury plays a central role in the death of dopaminergic neurons. Because LRRK2 affects process outgrowth, we anticipate that it will affect axonal transport either by altering the proteins which serve as transport tracks, the cargos being carried, the motor proteins responsible for moving the cargos or the production of energy required for transport. If so, these pathways will serve as new targets for therapeutic drugs.