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The Journal of Neuroscience, August 2, 2006, 26(31):8057-8068; doi:10.1523/JNEUROSCI.2261-06.2006

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Neurobiology of Disease
Induction of Autophagy in Axonal Dystrophy and Degeneration

Qing Jun Wang,^1,4 Yaomei Ding,⁴ Stave Kohtz,⁵ Noboru Mizushima,⁶ Ileana M. Cristea,¹ Michael P. Rout,² Brian T. Chait,¹ Yun Zhong,³ Nathaniel Heintz,³ and Zhenyu Yue⁴

Laboratories of ¹Mass Spectrometry and Gaseous Ion Chemistry, ²Cellular and Structural Biology, and ³Molecular Biology, Rockefeller University, New York, New York 10021, Departments of ⁴Neurology and Neuroscience and ⁵Pathology, Mount Sinai School of Medicine, New York, New York 10029, and ⁶Department of Bioregulation and Metabolism, Tokyo Metropolitan Institute of Medical Science, Tokyo 113-8613, Japan

Correspondence should be addressed to Zhenyu Yue, Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029. Email: zhenyu.yue{at}mssm.edu

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.

Key words: autophagy; neurodegeneration; MAP1B; LC3; axonal dystrophic swellings; Lurcher

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Received Dec. 18, 2005; accepted June 23, 2006.

Correspondence should be addressed to Zhenyu Yue, Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029. Email: zhenyu.yue{at}mssm.edu

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