Structural plasticity of actin-spectrin membrane skeleton and functional role of actin and spectrin in axon degeneration
Guiping Wang,
David J Simon,
Zhuhao Wu,
Deanna M Belsky,
Evan Heller,
Melanie K O'Rourke,
Nicholas T Hertz,
Henrik Molina,
Guisheng Zhong,
Marc Tessier-Lavigne,
Xiaowei Zhuang
Affiliations
Guiping Wang
Department of Chemistry and Chemical Biology, Howard Hughes Medical Institute, Harvard University, Cambridge, United States; Department of Physics, Howard Hughes Medical Institute, Harvard University, Cambridge, United States
Laboratory of Brain Development and Repair, The Rockefeller University, New York, United States; Department of Biology, Stanford University, Stanford, United States
Laboratory of Brain Development and Repair, The Rockefeller University, New York, United States
Deanna M Belsky
Department of Biology, Stanford University, Stanford, United States
Evan Heller
Department of Chemistry and Chemical Biology, Howard Hughes Medical Institute, Harvard University, Cambridge, United States; Department of Physics, Howard Hughes Medical Institute, Harvard University, Cambridge, United States
Melanie K O'Rourke
Department of Biology, Stanford University, Stanford, United States
Nicholas T Hertz
Laboratory of Brain Development and Repair, The Rockefeller University, New York, United States; Department of Biology, Stanford University, Stanford, United States
Henrik Molina
Proteomics Resource Center, The Rockefeller University, New York, United States
Guisheng Zhong
Department of Chemistry and Chemical Biology, Howard Hughes Medical Institute, Harvard University, Cambridge, United States; Department of Physics, Howard Hughes Medical Institute, Harvard University, Cambridge, United States
Marc Tessier-Lavigne
Laboratory of Brain Development and Repair, The Rockefeller University, New York, United States; Department of Biology, Stanford University, Stanford, United States
Department of Chemistry and Chemical Biology, Howard Hughes Medical Institute, Harvard University, Cambridge, United States; Department of Physics, Howard Hughes Medical Institute, Harvard University, Cambridge, United States
Axon degeneration sculpts neuronal connectivity patterns during development and is an early hallmark of several adult-onset neurodegenerative disorders. Substantial progress has been made in identifying effector mechanisms driving axon fragmentation, but less is known about the upstream signaling pathways that initiate this process. Here, we investigate the behavior of the actin-spectrin-based Membrane-associated Periodic Skeleton (MPS), and effects of actin and spectrin manipulations in sensory axon degeneration. We show that trophic deprivation (TD) of mouse sensory neurons causes a rapid disassembly of the axonal MPS, which occurs prior to protein loss and independently of caspase activation. Actin destabilization initiates TD-related retrograde signaling needed for degeneration; actin stabilization prevents MPS disassembly and retrograde signaling during TD. Depletion of βII-spectrin, a key component of the MPS, suppresses retrograde signaling and protects axons against degeneration. These data demonstrate structural plasticity of the MPS and suggest its potential role in early steps of axon degeneration.
