The neuronal cell nucleus has a characteristic and highly specialised organisation. The nucleolus appears to act as a central organising region around which there is a complex organisation of subnuclear structures, such as the perinucleolar â??rosetteâ?? and a large perinucleolar â??capâ?? of heterochromatin. We are currently defining the molecular and ultrastructural composition of these domains. The rosette is made up of 1-2 domains containing the Cajal Body protein p80 coilin together with Nopp140 and the SMN complex , the remainder contain Nopp140. The heterochromatin caps contain large areas of MeCP2 and are associated with smaller domains containing the chromosome centromeres or the polycomb protein complex. All these areas are variably marked by trimethylated histones. We are further defining this complex organisation by comparing it with 1) the spatial patterns of gene expression occurring in neurons in vivo and 2) the 3d spatial arrangement of genes within the nucleus of defined neurons Why do we think that this complex arrangement of neuronal nuclear structure is of importance for human neurological disease? We have shown that in Huntingtonâ??s disease the neuronal nucleus reorganises to accommodate a large intranuclear inclusion such that the perinucleolar rosette is disrupted to allow movement of the Cajal body like p80 coilin positve structure to attach to the newly formed inclusion. This results in a profound rearrangement of the nucleolar structure, dissociation away from defined chromosomal domains and transcriptional dysregulation. Similar disruption of these structures occurs in spinal muscular atrophy (SMA), fragile X tremor ataxia syndrome (FXTAS), frontotemporal dementia (FTD) and autism spectrum disorder (ASD). We are currently investigating the functional consequences of nuclear disruption in these conditions.