TY - JOUR
T1 - A deleterious mutation in DNAJC6 encoding the neuronal-specific clathrin-uncoating Co-chaperone auxilin, is associated with juvenile parkinsonism
AU - Edvardson, Simon
AU - Cinnamon, Yuval
AU - Ta-Shma, Asaf
AU - Shaag, Avraham
AU - Yim, Yang In
AU - Zenvirt, Shamir
AU - Jalas, Chaim
AU - Lesage, Suzanne
AU - Brice, Alexis
AU - Taraboulos, Albert
AU - Kaestner, Klaus H.
AU - Greene, Lois E.
AU - Elpeleg, Orly
PY - 2012/5/1
Y1 - 2012/5/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84860487766&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0036458
DO - 10.1371/journal.pone.0036458
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C2 - 22563501
AN - SCOPUS:84860487766
SN - 1932-6203
VL - 7
JO - PLoS ONE
JF - PLoS ONE
IS - 5
M1 - e36458
ER -