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The cytoskeleton in neurons is made up of three interacting structural complexes: microfilaments (MFs), neurofilaments (NFs), and microtubules (MTs). They serve multiple roles in neurons. First, they provide structural organization for the cell interior, helping to establish metabolic compartments. Second, they serve as tracks for intracellular transport, especially axonal transport, which is critical for neuronal survival. Finally, the cytoskeleton comprises the core framework of neuronal morphologies. Disorganization of the cytoskeleton network is a prominent cytopathological feature of several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), infantile spinal muscular atrophy (SMA), and Alzheimer diseases. Our major focus is to elucidate biological functions of cytoskeletal associated proteins in neurons and to define the cellular and molecular basis for how these proteins contribute to the structure and function of neurons. Cellular and molecular approaches are being employed both in vitro and in vivo. Our experimental models include: 1) transfection assays, 2) primary neuron cultures, 3) in vitro protein-protein interaction assays, 4) yeast two-hybrid screening, 5) specific gene targeting in mice. Defining the biological functions of cytoskeletal organizing proteins would significantly advance our understanding of pathogenesis of neurodegenerative disorders.