Autophagy lipidation machinery regulates axonal microtubule dynamics but is dispensable for survival of mammalian neurons

We report on a regulation of MT dynamics by AuTophaGy(ATG)-related proteins, which previously have been linked to the autophagy pathway

A. Negrete-Hurtado; M. Overhoff; S. Bera; E. De Bruyckere; K. Schätzmüller; M. J. Kye; C. Qin; M. Lammers; V. Kondylis; I. Neundorf; N. L. Kononenko

2020

Scholarcy highlights

  • Neurons maintain axonal homeostasis via employing a unique organization of the microtubule cytoskeleton, which supports axonal morphology and provides tracks for intracellular transport
  • The lack of apoptosis in ATG5 KO brains was supported by the absence of cleaved caspase activity, a phenotype which was reproduced in an in-vitro cortico-hippocampal culture system, where the deletion of ATG5 was driven via a tamoxifen-dependent activation of the CAG-Cre promoter
  • To elucidate whether this phenotype was a mere function of ATG5 or a more general phenomenon associated with a defective light chain 3 lipidation machinery, we deleted ATG16L1, another component of the LC3 lipid conjugation system
  • We show that ATG5 and ATG16L1 proteins, involved in LC3 lipid conjugation, are dispensable for survival of forebrain excitatory neurons
  • Together with the observation that the reduction of dynamic MTs diminishes the transport of axonal cargo, our results predict that decrease in MT dynamics under autophagy-deficient condition impairs retrograde axonal signaling required for synaptic plasticity
  • We found that level of stable MTs was significantly increased in autophagydeficient neurons, while the labile MTs, probed by an antibody against the tyrosinated tubulin, were reduced
  • Recent data have shown that MT-stabilizing drug Paclitaxel, which is used to treat a wide spectrum of tumors, including breast and ovarian cancer, causes dysregulation of brain-derived neurotrophic factor signaling accompanied by memory dysfunctions in mice and humans, akin to the loss of
  • L, m Spheroid area is decreased in eGFP-transfected ATG5 KO axons treated with Elks siRNA, compared to scr siRNA

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