אסיף מאגר המחקר החקלאי

A deleterious mutation in DNAJC6 encoding the neuronal-specific clathrin-uncoating Co-chaperone auxilin, is associated with juvenile parkinsonism

Year:

2012

Source of publication :

Authors :

Volume :

7

Co-Authors:

Edvardson, S., Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel
Cinnamon, Y., Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel
Ta-Shma, A., Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel
Shaag, A., Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel
Yim, Y.-I., Laboratory of Cell Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States
Zenvirt, S., Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel
Jalas, C., Bonei Olam, Center for Rare Jewish Genetic Disorders, Brooklyn, NY, United States
Lesage, S., CRICM, University Pierre et Marie Curie, INSERM, UMR-S975, CNRS UMR 7225, Hospital Pitié-Salpêtrière, Paris, France
Brice, A., CRICM, University Pierre et Marie Curie, INSERM, UMR-S975, CNRS UMR 7225, Hospital Pitié-Salpêtrière, Paris, France
Taraboulos, A., IMRIC, The Hebrew University-Hadassah Medical School, Jerusalem, Israel
Kaestner, K.H., Department of Genetics, Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, PA, United States
Greene, L.E., Laboratory of Cell Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States
Elpeleg, O., Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel

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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. © 2012 Edvardson et al.

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