Amyotrophic lateral sclerosis (ALS) is the most frequent motor neuron disease, which is characterized by the selective loss of the upper and lower motor neuron as well as the progressive muscle weakness and atrophy. 20% of the familial-ALS is caused by mutation of the Cu/Zn-superoxide dismutase (SOD1). More than 150 mutations were found in SOD1 gene related to ALS. Mutant SOD1 possesses a gain-of-function toxicity and induces cell stresses through its misfolding and abnormal accumulation. Cytoplasmic protein aggregates are observed in both SOD1-linked familial ALS cases and mutant SOD1 transgenic mice. Understanding how to recognize and regulate these mutants are critical to figure out the mechanisms underlying the SOD1-related ALS pathology. PICK1 (protein interacting with C-k...[ Read more ]

Amyotrophic lateral sclerosis (ALS) is the most frequent motor neuron disease, which is characterized by the selective loss of the upper and lower motor neuron as well as the progressive muscle weakness and atrophy. 20% of the familial-ALS is caused by mutation of the Cu/Zn-superoxide dismutase (SOD1). More than 150 mutations were found in SOD1 gene related to ALS. Mutant SOD1 possesses a gain-of-function toxicity and induces cell stresses through its misfolding and abnormal accumulation. Cytoplasmic protein aggregates are observed in both SOD1-linked familial ALS cases and mutant SOD1 transgenic mice. Understanding how to recognize and regulate these mutants are critical to figure out the mechanisms underlying the SOD1-related ALS pathology. PICK1 (protein interacting with C-kinase1) plays an important role in protein trafficking. In my study, PICK1 shows higher affinity to a proportion of pathogenic SOD1 mutants. Overexpressed PICK1 promotes the aggregate formation of mutant SOD1 which is labeled with autophagy adaptor p62. SOD1 mutants exhibit higher affinity to PICK1 compared to p62 which indicates that PICK1 may interfere the degradation of mutant SOD1. Animal study demonstrates that deletion of PICK1 slows the disease progress and improves the motor performance in the early stage but does not alter the ultimate outcome. The distinct function in different ALS stage can be also observed in autophagy. In conclusion, PICK1 may regulate the traffic of mutant SOD1 and ALS pathogenesis through influencing the function of autophagy.