Disassembly of nuclear inclusions in the dividing cell - a novel insight into neurodegeneration

Spinocerebellar ataxias and Huntington's disease are examples of neurodegen erative diseases caused by a trinucleotide repeat expansion, One hallmark o f such diseases is the formation of inclusion bodies (IBs) within neuronal tissue, Although these inclusions may play a pivotal role in the disease pr ocess, the reasons underlying their specific accumulation remain obscure, B y studying intranuclear IBs in dividing cells we demonstrate for the first time that inclusions such as those of ataxin-1 disperse during mitosis, thu s reducing the nuclear aggregate burden, IBs reform in the interphase nucle us. By high-resolution confocal microscopy we also show that inclusions com prise ordered structures capable of homotypic interactions. Unlike those of a non-pathologic protein, ataxin-1 inclusions were shown to be capable of non-specific protein sequestration, Our studies indicate that the specific accumulation of inclusions in terminally differentiated cells such as neuro ns is a direct consequence of their inability to divide and therefore provi des a key to explaining their persistence in neurodegenerative disease.