The hallmark histopathology in FXTAS includes the presence of ubiquitin-positive inclusions in neurons and astrocytes that is widespread throughout the brain. As a further parallel between human FXTAS and the CGG KI mice, both show the presence of ubiquitin-positive intranuclear inclusions in many regions of the brain [
24‐
26,
45]. The CGG
dut KI develops intranuclear inclusions in neurons in the cerebral cortex, olfactory nucleus, parafascicular thalamic nucleus, medial mammillary nucleus and colliculus inferior, cerebellum, amygdala and pontine nucleus cortex, hippocampus, hypothalamus, and in granule cells of the cerebellum (Figure
3) [
24,
28]. Inclusions in the dentate gyrus of the hippocampus are evident as early as 12 weeks of age [
29]. The number of inclusions in glia, including astrocytes and Bergmann glia, and their distribution in the brain are more limited, and not as numerous as found in postmortem FXTAS brain tissue [
14,
25]. In addition, the size of the inclusions correlates significantly with the age of CGG
dut KI mice, with smaller inclusions found in younger mice. Interestingly, the gradual increase in the size of the inclusions and the percentage of ubiquitin-positive neurons appear to parallel the progressive development of the neurological phenotype of FXTAS in humans [
16]. Brain regions showing the presence of intranuclear inclusions correlate with the clinical features in patients with symptomatic FXTAS. Importantly, inclusions are not limited to the nervous system, and are found in both human FXTAS and in the CGG
dut KI mouse in a variety of other tissues, including pancreatic, thyroid, adrenal gland, gastrointestinal, pituitary gland, pineal gland, heart and mitral valve. Inclusions were also found in the testes, epididymis and kidney of patients with FXTAS, but not in the KI mice [
46]. Therefore, FXTAS should be considered a multi-organ disease. Systematic analysis of these inclusions shows the presence of more than 20 proteins including ubiquitin, molecular chaperone Hsp40, 20S proteasome complex, DNA repair-ubiquitin-associated HR23B factor and SAM-68, DGCR8, and DROSHA [
18,
19,
24,
47‐
49]. The inclusions also contain
FMR1 mRNA, but surprisingly not FMRP [
18]. Similar studies on the protein composition of inclusions found in CGG mouse models have not been carried out, but it is already apparent that there are some similarities between the inclusions in FXTAS and mouse models, including the presence of ubiquitin, SAM68, DGCR8 and lamin A/C, as well as several differences [
18,
19,
24,
27,
47,
50]. Purα has been detected in intranuclear inclusions in a
Drosophila model of the premutation and overexpression can suppress CGG repeat-mediated neurodegeneration. However, purα has not yet been detected in inclusions in murine models and evidence for its presence in human inclusions is inconclusive [
18,
50]. Similarly, hnRNP-A2/B1 are found in the intranuclear inclusions in FXTAS [
18], but little or none has been found in CGG KI mice [
34]. Additional research on the composition of intranuclear inclusions in FXTAS and mouse models would clearly be of value.