Auxilin, clathrin trafficking and Parkinson's disease

Clathrin trafficking is crucial for cellular function in all eukaryotes and plays a specialized role in synaptic transmission in higher organisms. Clathrin-coated vesicles (CCVs) mediate selective transport of cargo from the plasma membrane and trans-Golgi network (TGN) to intracellular destinations. Auxilin is the major neuronal CCV uncoating protein required for successful delivery of cargo to its destination compartments. Whereas its role in the uncoating of CCVs at the synapse has been well-documented, the role of Auxilin in the uncoating of TGN-derived CCVs is less established. Parkinsons disease (PD) is a common neurodegenerative disorder, characterized in part by neuropathological lesions in the nigrostriatal pathway. Multiple loss of function mutations in the gene encoding Auxilin have been found to cause an aggressive form of young onset PD. However, the mechanism of action of the pathogenic Auxilin mutations remains to be elucidated. In this thesis, the impact of pathogenic Auxilin mutations was investigated in vivo and in cellular and molecular settings. A novel mouse model carrying the pathogenic R857G Auxilin mutation was found to display neurological phenotypes that phenocopy clinical features seen in patients, including seizures and motor impairments. Mapping the interactome of Auxilin led to the identification of novel bona fide TGN-resident interactors. Impaired clathrin trafficking in R857G Auxilin mice, both at the synapse and the TGN, was found to result in neuropathological lesions in the nigrostriatal pathway. Taken together, the work presented in this thesis provides novel insights in the physiological role of Auxilin as well as PD pathogenesis in Auxilin mutation carriers. In addition, these data underscore an important role for clathrin trafficking in PD.