LIFS Seminar Series “Coatopathies: Genetic Disorders of Protein Coats” by Prof. Juan S. Bonifacino

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LIFS Seminar Series “Coatopathies: Genetic Disorders of Protein Coats” by Prof. Juan S. Bonifacino

December 21, 2018 @ 4:00 pm - 5:30 pm HKT

Prof. Juan S. Bonifacino
National Institutes of Health, Bethesda, Maryland, USA


Transport of cargo between different compartments of the endomembrane system of eukaryotic cells depends on protein coats that mediate cargo sorting and transport vesicle formation at the donor compartment. Mutations in components of these protein coats are the cause of various genetic disorders that we refer to as “coatopathies”. We have recently studied the mechanism by which mutations in the AP-4 coat cause a complicated form of hereditary spastic paraplegia (HSP) termed “AP-4-deficiency syndrome”. The HSPs are a clinically and genetically heterogeneous group of disorders characterized by progressive lower limb spasticity (i.e., leg stiffness). In addition to lower limb spasticity, AP-4-deficiency syndrome features intellectual disability, microcephaly, seizures, thin corpus callosum and upper limb spasticity (i.e., tetraplegia). To investigate the pathogenesis of AP-4 deficiency syndrome, we characterized a knockout (KO) mouse for the AP4E1 gene encoding the epsilon subunit of AP-4. We found that AP-4-epsilon-KO mice exhibit a range of neurological phenotypes, including hindlimb clasping, decreased motor coordination and weak grip strength. In addition, AP-4 ε KO mice display a thin corpus callosum and axonal swellings in various areas of the brain and spinal cord. Immunohistochemical analyses showed that the transmembrane autophagy protein ATG9A is more concentrated in the trans-Golgi network (TGN) and depleted from the peripheral cytoplasm both in skin fibroblasts from patients with mutations in the μ4 subunit of AP-4 and in various neuronal types in AP-4 epsilon KO mice. ATG9A mislocalization was associated with an increased tendency to accumulate protein aggregates in the axon of AP-4 epsilon KO neurons. These findings indicate that the AP-4 epsilon KO mouse is a suitable animal model for AP-4 deficiency syndrome, and that defective export of ATG9A from the TGN and impaired autophagic degradation of protein aggregates might contribute to neuroaxonal dystrophy in this disorder.

(Host faculty: Prof. Yusong Guo)


December 21, 2018
4:00 pm - 5:30 pm
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