Neuronal Cytoskeleton Regulation and Neurodegeneration

The biology of neurodegeneration program evolved from the laboratory studying the basic biology of neuronal cytoskeletal protein phosphorylation during development and normal function in the adult. To understand the molecular basis of neurodegeneration, our major focus has been to study the regulation of compartment-specific patterns of cytoskeletal protein phosphorylation in neuronal perikarya and axons. We have demonstrated that the phosphorylation of the numerous acceptor sites on proline-directed serine and thronine (Pro-Ser/Thr) residue proteins such as tau and neurofilaments is tightly regulated. The phosphorylation of these molecules is generally confined to the axonal compartment. It was recognized that in neurodegenerative disorders such as Alzheirner's disease (AD) and amyotrophic lateral sclerosis (ALS), the pathology was characterized by an accumulation of aberrantly phosphorylated cytoskeletal proteins in cell bodies, suggesting that topographic regulation had been compromised. This led inevitably into studies of neurodegeneration in cell culture and model mice with emphasis on a specific neuronal protein kinases, for example, cyclin-dependent kinase 5 (Cdk5), that target numerous neuronal proteins including cytoskeletal proteins, which when deregulated may be responsible for the pathology seen in neurodegeneration. In cell systems, neuronal stress leads to deregulated kinases, for example, Cdk5, accompanied by abnormal cytoskeletal protein phosphorylation and cell death characteristic of neurodegeneration. In this chapter, efforts are made to answer some of the following questions. (1) How is the cytoskeletal protein phosphorylation topographically and stably regulated in their proline-directed Ser/Thr residues in neurons? (2) What factors are responsible for the regulation and deregulation of Cdk5 in neurons?