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.
Highlights
Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease characterized by predominant loss of motor neurons in the spinal cord, brain stem, and motor cortex [1]
Our study suggests that dysfunction of associated kinase 1 (AAK1) resulting in dis-regulation of endosomal and synaptic vesicle recycling pathway is likely involved in ALS pathology
Immunoprecipitation experiment using the synaptosomal preparations isolated from SOD1G85R transgenic mouse spinal cord tissues did not result in detectable levels of interactions between AAK1 and SOD1G85R in the mammalian content (Figure S2)
Summary
Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease characterized by predominant loss of motor neurons in the spinal cord, brain stem, and motor cortex [1]. The availability of rodent models of ALS by overexpression of the mutant forms of SOD1 has made it possible to investigate pathogenesis of SOD1-linked ALS. Mechanisms of how mutations in SOD1 cause ALS remain elusive, it is evident that mutant SOD1s gain toxic properties independent of the enzyme activity that result in ALS pathology [3]. One underlying mechanism that is consistent with gained toxic properties of mutant SOD1s causing disease is their abilities to interact with new proteins that the wild-type (WT) SOD1 (SOD1WT) normally does not. These were the findings from several studies that could explain the gained toxicities
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