Induction of autophagy in axonal dystrophy and degeneration.
Autophagy is a highly regulated cellular mechanism for the bulk degradation of cytoplasmic contents. It has been implicated in a variety of physiological and pathological conditions relevant to neurological diseases. However, the regulation of autophagy in neurons and its role in neuronal and axonal pathology are not yet understood. Using transgenic mice producing green fluorescent protein-tagged autophagic marker microtubule-associated protein light chain 3 (GFP-LC3), we provide molecular evidence for the induction of autophagy in axonal dystrophy and degeneration in Purkinje cells of the Lurcher mice, a model for excitotoxic neurodegeneration. We show that the excitotoxic insult of Lurcher mutation triggers an early response of Purkinje cells involving accumulation of GFP-LC3-labeled autophagosomes in axonal dystrophic swellings (a hallmark of CNS axonopathy). In brain, LC3 interacts with high affinity with the microtubule-associated protein 1B (MAP1B). We show that MAP1B binds to LC3 of both cytosolic form (LC3I) and lipidated form (LC3II). Moreover, in cell culture, overexpression of MAP1B results in reduced LC3II levels and number of GFP-LC3-labeled autophagosomes; phosphorylated MAP1B is associated with GFP-LC3-labeled autophagosomes. Furthermore, in brain, phosphorylated MAP1B accumulates in axonal dystrophic swellings of degenerating Purkinje cells and binds to LC3 at increased level. Therefore, the MAP1B-LC3 interaction may participate in regulation of LC3-associated autophagosomes in neurons, in particular at axons, under normal and pathogenic conditions. We propose that induction of autophagy serves as an early stress response in axonal dystrophy and may participate in the remodeling of axon structures.
Wang
Qing Jun
QJ
Laboratory of Mass Spectrometry and Gaseous Ion Chemistry, Rockefeller University, New York, New York 10021, USA.
Ding
Yaomei
Y
Kohtz
D Stave
DS
Kohtz
Stave
S
Mizushima
Noboru
N
Cristea
Ileana M
IM
Rout
Michael P
MP
Chait
Brian T
BT
Zhong
Yun
Y
Heintz
Nathaniel
N
Yue
Zhenyu
Z
D000818:Animals; D001343:Autophagy; D001369:Axons / Q000473:pathology*; D002478:Cells, Cultured; D051379:Mice; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000473:pathology*; D010588:Phagosomes / Q000473:pathology*; D011689:Purkinje Cells / Q000473:pathology*; D012183:Retrograde Degeneration / Q000473:pathology*