Are there multiple pathways in the pathogenesis of Huntington's disease?

Studies of huntingtin localization in human post-mortem brain offer insight s and a framework for basic experiments in the pathogenesis of Huntington's disease. In neurons of cortex and striatum, we identified changes in the c ytoplasmic localization of huntingtin including a marked perinuclear accumu lation of huntingtin and formation of multivesicular bodies, changes concei vably pointing to an altered handling of huntingtin in neurons. In Huntingt on's disease, huntingtin also accumulates in aberrant subcellular compartme nts such as nuclear and neuritic aggregates co-localized with ubiquitin. Th e site of protein aggregation is polyglutamine-dependent, both in juvenile- onset patients having more aggregates in the nucleus and in adult-onset pat ients presenting more neuritic aggregates. Studies in vitro reveal that the genesis of these aggregates and cell death are tied to cleavage of mutant huntingtin. However, we found that the aggregation of mutant huntingtin can be dissociated from the extent of cell death. Thus properties of mutant hu ntingtin more subtle than its aggregation, such as its proteolysis and prot ein interactions that affect vesicle trafficking and nuclear transport, mig ht suffice to cause neurodegeneration in the striatum and cortex. We propos e that mutant huntingtin engages multiple pathogenic pathways leading to ne uronal death.