Journal Article

A Deleterious Mutation in DNAJC6 Encoding the Neuronal-Specific Clathrin-Uncoating Co-Chaperone Auxilin, Is Associated with Juvenile Parkinsonism

Lesage, Suzanne, Kaestner, Klaus H., Ta-Shma, Asaf, Jalas, Chaim, Brice, Alexis, Elpeleg, Orly, Cinnamon, Yuval, Yim, Yang-In, Greene, Lois E., Zenvirt, Shamir, Taraboulos, Albert, Shaag, Avraham, Edvardson, Simon

2012

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adenosine triphosphatase / Adenosinetriphosphatase / Adolescent / ATPases / Auxilins - genetics / Auxilins - metabolism / Base Sequence / Biology / Brain diseases / Cages / Chaperones / Clathrin / Clathrin - metabolism / Consortia / Dementia / DNA Mutational Analysis - methods / Dopamine / Endocytosis / Family Health / Fatty acids / Fibroblasts / Genes / Genetic aspects / Genetic research / Genomics / Heat shock proteins / Homozygosity / Hsc70 protein / HSP40 Heat-Shock Proteins - genetics / HSP40 Heat-Shock Proteins - metabolism / Hsp40 protein / Humans / Identification / Laboratories / Male / Medicine / Molecular Chaperones - genetics / Molecular Chaperones - metabolism / Movement disorders / Muscles / Mutation / Neurodegenerative diseases / Neurons / Neurons - metabolism / Parkinson disease / Parkinson's disease / Parkinsonian Disorders - genetics / Parkinsons disease / Pathogenesis / Patients / Pedigree / Posture / Protein turnover / Proteins / RNA / Segregation / Substantia nigra / Synaptic vesicles / Uncoating