chapter  2
26 Pages

Chapter Huntington’s Disease Pathogenesis: Mechanisms and Pathways

The discovery in 1993 of the gene responsible for Huntington’s disease (HD) represented a crucial turning point in the HD research eld. At the time of the discovery, no one could predict that HD would belong to a large class of inherited neurological diseases all caused by the same type of genetic mutation (i.e., polyglutamine [polyQ] expansion) or that the mechanistic basis of HD (i.e., protein misfolding) would emerge as a common theme linking together all the major neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and the prion diseases. The study of how the mutant HD gene product, an unusually large 3,144 amino acid protein (huntingtin [htt]) with few recognizable motifs or obvious functional domains that results in the degeneration and death of neurons in the striatum

Introduction ..............................................................................................................29 Protein Aggregation and Degradation ......................................................................30 Proteolytic Cleavage ................................................................................................ 33 Transcriptional Dysregulation .................................................................................. 33

Mechanisms of Huntingtin-Mediated Transcriptional Interference ...............34 Evidence for Mitochondrial Abnormalities and Defective Energy

Metabolism in HD .......................................................................................... 35 Linking Transcription Interference with Mitochondrial Bioenergetic

Abnormalities .....................................................................................36 Neurotrophic Factors ............................................................................................... 38 Cytoskeletal Defects and Axonal Transport ............................................................. 39 A Role for the Loss of Huntington Normal Function in HD? ................................. 42 Non-Cell Autonomous Degeneration in HD ............................................................ 43 Neuroin ammation in HD: How Important Are Microglia? ...................................44 Conclusions ..............................................................................................................46 Acknowledgments ....................................................................................................46 References ................................................................................................................46