A Deleterious Mutation in DNAJC6 Encoding the Neuronal-Specific Clathrin-Uncoating Co-Chaperone Auxilin, Is Associated with Juvenile Parkinsonism
Open Access
- 1 May 2012
- journal article
- case report
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 7 (5), e36458
- https://doi.org/10.1371/journal.pone.0036458
Abstract
Parkinson disease is caused by neuronal loss in the substantia nigra which manifests by abnormality of movement, muscle tone, and postural stability. Several genes have been implicated in the pathogenesis of Parkinson disease, but the underlying molecular basis is still unknown for ∼70% of the patients. Using homozygosity mapping and whole exome sequencing we identified a deleterious mutation in DNAJC6 in two patients with juvenile Parkinsonism. The mutation was associated with abnormal transcripts and marked reduced DNAJC6 mRNA level. DNAJC6 encodes the HSP40 Auxilin, a protein which is selectively expressed in neurons and confers specificity to the ATPase activity of its partner Hcs70 in clathrin uncoating. In Auxilin null mice it was previously shown that the abnormally increased retention of assembled clathrin on vesicles and in empty cages leads to impaired synaptic vesicle recycling and perturbed clathrin mediated endocytosis. Endocytosis function, studied by transferring uptake, was normal in fibroblasts from our patients, likely because of the presence of another J-domain containing partner which co-chaperones Hsc70-mediated uncoating activity in non-neuronal cells. The present report underscores the importance of the endocytic/lysosomal pathway in the pathogenesis of Parkinson disease and other forms of Parkinsonism.Keywords
This publication has 27 references indexed in Scilit:
- α-Synuclein Interacts with Glucocerebrosidase Providing a Molecular Link between Parkinson and Gaucher DiseasesOnline Journal of Public Health Informatics, 2011
- A Mutation in VPS35, Encoding a Subunit of the Retromer Complex, Causes Late-Onset Parkinson DiseaseAmerican Journal of Human Genetics, 2011
- VPS35 Mutations in Parkinson DiseaseAmerican Journal of Human Genetics, 2011
- A Two-Stage Meta-Analysis Identifies Several New Loci for Parkinson's DiseasePLoS Genetics, 2011
- Endocytosis and clathrin-uncoating defects at synapses of auxilin knockout miceProceedings of the National Academy of Sciences of the United States of America, 2010
- Cargo and Dynamin Regulate Clathrin-Coated Pit MaturationPLoS Biology, 2009
- α‐Synuclein and Polyunsaturated Fatty Acids Promote Clathrin‐Mediated Endocytosis and Synaptic Vesicle RecyclingTraffic, 2009
- Auxilin Depletion Causes Self‐Assembly of Clathrin into Membraneless Cages In VivoTraffic, 2008
- Deleterious Mutation in the Mitochondrial Arginyl–Transfer RNA Synthetase Gene Is Associated with Pontocerebellar HypoplasiaAmerican Journal of Human Genetics, 2007
- Multiple Interactions of Auxilin 1 with Clathrin and the AP-2 Adaptor ComplexOnline Journal of Public Health Informatics, 2001