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

Spinocerebellar ataxias and Huntington's disease are examples of neurodegenerative diseases caused by a trinucleotide repeat expansion, One hallmark of such diseases is the formation of inclusion bodies (IBs) within neuronal tissue, Although these inclusions may play a pivotal role in the disease process, the reasons underlying their specific accumulation remain obscure, By studying intranuclear IBs in dividing cells we demonstrate for the first time that inclusions such as those of ataxin-1 disperse during mitosis, thus reducing the nuclear aggregate burden, IBs reform in the interphase nucleus. By high-resolution confocal microscopy we also show that inclusions comprise 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 neurons is a direct consequence of their inability to divide and therefore provides a key to explaining their persistence in neurodegenerative disease.