CME is a major pathway for the internalization of selected protein cargo from the plasma membrane to membrane-bound internal compartments. The cargo, mainly receptors and their bound ligands, is recruited to nascent clathrin-coated pits, which then mature, invaginate, and ultimately undergo fission to produce Clathrin-Coated Vesicles (CCVs) 
. Once the vesicle has pinched off from the plasma membrane, the coat is lost and its components are recycled. The vesicle itself then fuses with the membrane of a target compartment. The shedding of the coat, which occurs almost immediately after the endocytic CCV buds from the plasma membrane, is driven by ATP hydrolysis and is important for clathrin recycling 
. The necessary ATPase activity is contributed by Hsc70, which like all Hsp70 homologues, interacts with J-domain containing cochaperones that specify its targets. In the case of clathrin coats, the relevant J-domain protein is Auxilin 
. Three functional domains are instrumental for Auxilin's co-chaperone activity: an N-terminal PTEN-like domain (residues 40–421), which is important for recruitment of Auxilin onto CCVs, a middle domain which binds clathrin, and a carboxyl-terminal J-domain (residues 886–931) which binds Hsc70 
. The low mRNA level in our patients and the production of two abnormal transcripts lacking either a significant part of the PTEN-like domain or the carboxyl-terminal J-domain, suggest that cells homozygous for the c.801-2 A−>G mutation lack the Auxilin protein.
Auxilin is selectively expressed in neurons and is enriched in nerve terminals 
. In non-neuronal cells, another J-domain containing partner, the ubiquitously expressed cyclin-G-dependent kinase (GAK), co-chaperones Hsc70-mediated uncoating activity on CCV 
. Reduction of Auxilin and its homologue GAK was shown to result in the impairment of CME and of the clathrin-dependent traffic of cargo from the Golgi to the lysosome 
. Nonetheless, Auxilin is not redundant in mice and Auxilin null mice exhibit an abnormally increased retention of assembled clathrin on vesicles and in empty cages despite upregulation of GAK. This defect, in turn, leads to impaired synaptic vesicle recycling and perturbed CME, probably because of sequestration of clathrin coat components and their accessory factors with failure to form new clathrin-coated pits 
. Mice lacking Auxilin have a high rate of unexplained early postnatal mortality, and surviving pups fail to thrive though they do have normal life span. We examined brain tissue of these Auxilin null mice but could not detect any alteration in substantia nigra morphology, dopamine transporter abundance or distribution (data not shown), in agreement with the lack of any gait or movement abnormalities in the mutant mice. Lack of neurodegeneration in transgenic mice that express mutated versions of PD genes is a recognized phenomenon in PD research 
The identification of the molecular basis of familial PD and juvenile variants is still in progress 
. Loss of-function mutations in PRKN, PINK1
, and DJ-1
, all implicated in mitochondrial repair/elimination machinery, give rise to a pure, early onset PD. Another group of PD-causing genes participate in the endosomal/lysosomal pathway. α-synuclein, encoded by SNCA
, was shown to participate in synaptic vesicle formation and recycling and to facilitate CME 
. The C. elegance
orthologue of LRRK2, another central player in PD pathogenesis, regulates the proper localization of synaptic vesicles in neurons 
. Dominant mutations in PD patients were recently identified in VPS35
, a component of the retromer complex which mediates retrograde transport between endosomes and the trans-Golgi network 
. Another player in the endosomal/lysosomal compartment, ATP13A2, is also associated with PD 
. Finally, mutations in the gene encoding the lysosomal enzyme glucocerebrosidase, which interacts with α-synuclein 
, have also been identified as PD susceptibility alleles 
. The involvement of these five genes underscores the role of the endosomal/lysosomal pathway in PD pathogenesis. We propose that Auxilin is a new endosomal/lysosomal Parkinsonism-related gene. We refrain from the term “Parkinson Disease" since the patients did not respond to L-Dopa. Since dopamine receptors undergo CME 
followed by endosomal sorting to recycling or degradation 
, it is conceivable that a homozygous deleterious mutation in the Auxilin encoding gene, DNAJC6
, would give rise to abnormal dopamine receptor metabolism with the resultant parkinsonism. We studied the endosomal system in fibroblasts of patient II-2 by measuring transferrin uptake but observed no differences in either the levels or the pattern of transferrin uptake between control and mutant cells suggesting that in human fibroblasts Auxilin is redundant and its activity overlaps that of GAK.
does not fall within any of the peaks discovered by recent PD genome-wide association studies. Focused studies on common variation in this gene are perhaps now warranted 
. We determined the sequence of the coding exons and splice sites of DNAJC6
in 15 patients with PD onset before 40 years of age but could not find any pathogenic mutation.
In summary, using homozygosity mapping in a consanguineous small family, followed by whole exome sequencing of a single patient who suffered from juvenile Parkinsonism, we were able to identify a new Parkisnsonism-related gene. It is likely that DNAJC6 is indispensible in the human substatia nigra but is redundant in peripheral tissues. Nevertheless, the findings presented above are important for the genetic counseling of the patient's extended family, and emphasize the role of CME in the pathogenesis of PD.