7.Neuronal Cytoskeleton Regulation and Neurodegeneration医学电子书.pdfVIP

Neuronal Cytoskeleton Regulation and Neurodegeneration Ya-Li Zheng, Niranjana D. Amin, Parvathi Rudrabhatla, Sashi Kesavapany, and Harish C. Pant Abstract The biology of neurodegeneration program evolved from the laboratory studying the basic biology of neuronal cytoskeletal protein phosphorylation dur- ing 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 numer- ous 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 Alzheimer’s disease (AD) and amyo- trophic 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 neu- ronal protein kinases, for example, cyclin-dependent kinase 5 (Cdk5), that target numerous neuronal proteins including cytoskeletal proteins, which when deregu- lated may be responsible for the pathology seen in neurodegeneration. In cell sys- tems, 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 follow- ing questions. (1) How is the cytoskeletal protein phosphorylation topographically and stably regulated in their proline-directed