Trafficking Defects in Huntington's Disease

Malfunctions of the membrane-trafficking machinery are emerging as defects associated with a number of neurodegenerative diseases, including Huntington's disease (HD). HD is a hereditary and progressive neurodegenerative disorder in which the underlying mutation is a CAG expansion within the coding sequence of the gene. This mutation is referred to as trinucleotide expansion, because the number of CAG triplets present in a mutated gene is greater than the number of CAG triplets found in a normal gene. HD is an autosomal dominant disease; therefore, the expanded CAG repeat is usually present in only one of the two alleles in the cell. Unaffected individuals may have 6 to 25 CAG triplets in both alleles. In HD patients, the disease allele typically contains 36 to 120 CAG triplets. The HD protein called huntingtin (htt) contains a polymorphic glutamine repeat at its N-terminus. As the CAG repeat number grows, the growing polyglutamine tract produces htt with increasingly aberrant properties and leads to selective neuronal death in the striatum. Neurons that are particularly affected in HD are located in the cerebral cortex and the caudate/putamen. Loss of brain cells in these regions causes memory deficits and uncontrolled muscle movements. Once the symptoms begin, death usually occurs within 15 to 20 years. This chapter reviews data that implicate defects in vesicle trafficking as a causative factor leading to toxicity in HD. The chapter specifically focuses on three points: the interactions that implicate htt as a trafficking protein, the way in which trafficking defects arise from the expression of the mutant form of htt (mhtt), and whether defective trafficking is a cause or consequence of toxicity.