DNAJC6/Auxilin mutations and Parkinson's disease

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We have used genome editing to introduce mutations in the human and mouse genome in the gene DNAJC6 that are associated with a familial, early onset complex form of Parkinson's disease (PD). Because the encoded protein, auxilin, is expressed in neurons, we have focussed on showing how behavior is affected by mutations. Mice show a subtle but significant motor phenotype as they age. We do not loss of neurons, suggesting that neuronal dysfunction occurs without overt neurodegeneration. Mechanistically, we have found that mutations allow for interaction with clathrin but not clathrin adaptor proteins that are present at both synapse and the Golgi. We see lipid accumulations that may relate to Golgi dysfunction, although this is not proven at this time. Our ongoing work in this project will be to further develop a more aggressive model with stronger neurodegenerative phenotypes.