This application combines biochemical, morphological and autoradiographic techniques to study slow axonal transport in normal and experimental conditions as well as the mechanism of action of compounds which specifically affect organization and transport of axonal cytoskeletal components. Three projects are proposed. Project 1: The distribution of proteins transported with the component b of the slow transport (SCb) in the transverse plane of the axon will be studied by quantitative autoradiography in animals treated wih b,b'-iminodipropionitrile (IDPN), a toxic compound that produces a segregation of axonal neurofilaments (NF) from microtubules (MT).
The aim of this project is to examine the role played by NF and/or MT in the translocation of SCb. Project 2: Slow axonal transport is investigated in the R2 giant neuron of Aplysia californica under normal conditions and following treatment with IDPN and other toxic compounds affecting NF transport.
The aim of this project is to take advantage of a enirely dissectable system to investigate a) basic aspects of slow axonal transport such as changes of cytoskeletal proteins during axonal transport along the most proximal regions of the axon; b) pathogenetic aspects of the NF axonopathies such as formation of NF containing enlargement. These studies cannot be performed in more complex axonal systems. Project 3: deals with the mechanism(s) of action of chemical compounds specifically affecting slow axonal transport and cytoskeletal organization. Possible interactions of neurotoxic compounds with NF and other cytoskeletal proteins and the molecular mechanism involved in the increased rate of NF transport, a characteristic effect of some of these compounds, will be investigated. The understanding the molecular basis of the experimental giant neuropathies may help clarify the pathogenesis of similar human diseases.
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