23 - Cytoplasmic Dynein Dysfunction and Neurodegenerative Disease

Abstract

Active, directed transport along cytoplasmic microtubules is a characteristic feature of mammalian cells. The transport of organelles, vesicles, and proteins along the microtubule cytoskeleton is driven by both kinesins and cytoplasmic dynein. Neurons are uniquely vulnerable to defects in dynein function. Mutations in cytoplasmic dynein and its activator dynactin result in neurological defects in humans as well as in model organisms including drosophila and mice. The important role of the dynein motor in intracellular trafficking and transport makes it likely that defects in this pathway contribute to a number of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD). The identification of cytoplasmic dynein as an essential minus-end-directed motor in higher eukaryotes has led to a much deeper understanding of the role of active transport in the neuron. This chapter reviews the critical roles dynein plays in neurons. Following this, it discusses the effects that dynein and dynactin mutations have on neuronal function. Finally, it deals with the neurodegenerative diseases in which dynein dysfunction is not the proximal cause but may be a key contributor to the pathological state. The significance of these questions to neurodegenerative disease is becoming increasingly clear with the identification of human mutations in the dynein-associated protein dynactin, Lis1, Rab7, and bIII spectrin, which is now a rapidly progressing field.