SEP 21, 2022 7:30 AM PDT

Keynote Presentation: Pathogenetic Mechanisms of Neurodevelopmental Disorders Caused by Dysfunction of Intracellular Transport with Live Q&A

C.E. Credits: P.A.C.E. CE Florida CE
  • Juan S. Bonifacino, PhD

    Associate Scientific Director Neurosciences and Cellular and Structural Biology Division (NCSBD) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) National Institutes of Health (NIH)


Heterotetrameric adaptor protein (AP) complexes play key roles in protein sorting and transport vesicle formation in the endomembrane system of eukaryotic cells. One of these complexes, AP-4, was identified over 20 years ago but, until recently, its function remained unclear. AP-4 associates with the trans-Golgi network (TGN) through interaction with small GTPases of the ARF family. Recent studies identified the autophagy protein ATG9A as a specific AP-4 cargo. Defective export of ATG9A from the TGN in AP-4-deficient cells was shown to reduce ATG9A delivery to pre-autophagosomal structures, impairing autophagosome maturation. In addition, mutations in AP-4-subunit genes were found to cause neurological dysfunction in mice and a form of complicated hereditary spastic paraplegia referred to as 'AP-4-deficiency syndrome' in humans. These findings demonstrated that mammalian AP-4 is required for the development and function of the central nervous system, likely through its role in the sorting of ATG9A for the maintenance of autophagic homeostasis. In my talk, I will review the properties and functions of AP-4, and discuss how they might explain the clinical features of AP-4 deficiency.

Learning Objectives:

1. Classify how adaptor protein (AP) complexes mediate protein sorting to different intracellular compartments.
2. Analyze the connection of the AP-4 complex to autophagy, development of the central nervous system, and neurodevelopmental disease.
3. Express how to go from basic research discoveries to the elucidation of pathogenetic mechanisms and potential therapies.

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