NOV 19, 2019 10:00 AM PST

LC3-associated endocytosis: guarding against neuroinflammation & neurodegeneration

Sponsored by: Miltenyi Biotec
C.E. Credits: P.A.C.E. CE Florida CE
Speaker
  • John H. Sununu Endowed Fellow in Immunology St. Jude Children's Research Hospital Memphis, TN USA
    Biography
      Dr. Heckmann's research is focused on understanding the regulation of immune function in the central nervous system. Under the mentorship of Dr. Douglas Green, Immunology Chair at St. Jude, Dr. Heckmann identified a novel cellular trafficking pathway that uses a subset of the autophagy proteins to conjugate the microtubule-associated protein LC3 to endosomes, a process they termed LC3-associated endocytosis or LANDO. Moreover, Dr. Heckmann identified this novel mechanism to be a critical protective factor against amyloid deposition, neuroinflammation, and neurodegeneration in a murine model of Alzheimer's Disease. Prior to his current work, Dr. Heckmann received his bachelor's degree in Biology from the University of Kentucky where he studied the role of canonical autophagy in mammalian development. He subsequently completed his graduate training in molecular biology and biochemistry at the Mayo Clinic College of Medicine where he studied global metabolic regulation by pathways including autophagy and lipolysis. As a doctoral student he elucidated the transcriptional and post-translational regulation of the lipolytic inhibitor G0/G1 switch gene 2 (G0S2) and the importance of the G0S2 protein in regulating hepatic lipid accumulation. In a seminal discovery, Dr. Heckmann showed that increased expression of G0S2 regulated by LXR-alpha in liver promoted the establishment of non-alcoholic steatohepatitis. His past and present work have led to multiple high impact publications including the most recent work on LANDO being featured in Cell. Likewise, he has been the recipient of multiple awards and honors including a European Cell Death Organization Scholarship, the AAAS Excellence in Science Award, the Ruth L. Kirschstein National Research Service Award, and has most recently has been nominated for the 2019 Science Prize in Neurobiology, presented by Eppendorf.

    Abstract

    DATE: November 19, 2019
    TIME: 10:00am PST

    Microglial cells are the resident innate immune cells of the central nervous system (CNS) and are responsible for regulating inflammatory activation in response to both physiological and pathological immune perturbations. The mechanisms that fully control and dictate the nature of an inflammatory response in the CNS are still poorly understood. We have recently identified a novel pathway where components of the canonical autophagy machinery function to conjugate the microtubule-associated protein LC3 to endosomal membranes, a process we have termed LC3-associated endocytosis (LANDO). We further identified that abrogation of LANDO in microglial cells promotes pro-inflammatory cytokine production in vitro. To characterize LANDO and its role in immune regulation in the CNS, we utilized a well-established model of neuroinflammation induced by β-amyloid deposition. We found that mice lacking LANDO but not canonical autophagy in either the myeloid compartment or specifically in microglia, have a robust increase in pro-inflammatory cytokine production in the hippocampus and have increased levels of neurotoxic β-amyloid accumulation. This inflammation and β-amyloid deposition led to reactive microgliosis and hyperphosphorylation of tau, a protein that is vital to neuronal structure and function. As a consequence, LANDO-deficient Alzheimer’s Disease mice have increased neurodegeneration, resulting in impaired neuronal signaling and consequential behavioral and memory deficits. Mechanistically, β-amyloid is internalized by microglial cells through receptor-mediated endocytosis using a variety of surface receptors including Trem2 and CD36. We further identified that LANDO-deficiency not only alters immune activation upon endocytosis of β-amyloid, but results in impaired receptor recycling and extracellular β-amyloid accumulation. Exacerbation of β-amyloid accumulation further contributes to increased neuroinflammation. Together, our data support a protective role for LANDO in microglial cells of the CNS in neurodegenerative pathologies resulting from amyloid deposition.

     

    Learning Objectives:

    • Explain the regulation of neuroimmune functions of microglia and the role of the autophagy proteins in governing this process.
    • Elucidate novel therapeutic strategies and targets for neurodegenerative diseases including Alzheimer’s Disease.

     

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