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Int. J. Mol. Sci. 2014, 15(12), 22918-22932; doi:10.3390/ijms151222918

Dysfunction of Endocytic Kinase AAK1 in ALS

1
Department of Neuroscience, California Pacific Medical Center Research Institute, San Francisco, CA 94107, USA
2
Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA
3
Department of Biological Sciences, Xi'an Jiaotong-Liverpool University, Suzhou 215123, China
*
Author to whom correspondence should be addressed.
Received: 19 September 2014 / Revised: 1 December 2014 / Accepted: 3 December 2014 / Published: 10 December 2014
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Abstract

Mechanisms of human mutant superoxide dismutase 1 (SOD1)-induced toxicity in causing the familial form of amyotrophic lateral sclerosis (ALS) remain elusive. Identification of new proteins that can selectively interact with mutant SOD1s and investigation of their potential roles in ALS are important to discover new pathways that are involved in disease pathology. Using the yeast two-hybrid system, we identified the adaptor-associated kinase 1 (AAK1), a regulatory protein in clathrin-coated vesicle endocytic pathway that selectively interacted with the mutant but not the wild-type SOD1. Using both transgenic mouse and rat SOD1-linked familial ALS (FALS) models, we found that AAK1 was partially colocalized with the endosomal and presynaptic protein markers under the normal physiological condition, but was mislocated into aggregates that contained mutant SOD1s and the neurofilament proteins in rodent models of ALS in disease. AAK1 protein levels were also decreased in ALS patients. These results suggest that dysfunction of a component in the endosomal and synaptic vesicle recycling pathway is involved in ALS pathology. View Full-Text
Keywords: SOD1; ALS; AAK1; endocytosis; aggregates SOD1; ALS; AAK1; endocytosis; aggregates
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Shi, B.; Conner, S.D.; Liu, J. Dysfunction of Endocytic Kinase AAK1 in ALS. Int. J. Mol. Sci. 2014, 15, 22918-22932.

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