Pathology of CAG repeat diseases

Abstract

Neuronal intranuclear inclusions have become the neuropathological signature of the CAG repeat diseases, although their cytotoxicity is a matter of controversy. It has been demonstrated that the inclusions in dentatorubral-pallidoluysian atrophy (DRPLA) and Machado-Joseph disease (MJD) were immunopositive for several transcription factors such as TATA-binding protein (TBP), TBP-associated factor (TAF(II)130), Sp1, cAMP-responsive element-binding protein (CREB) and CREB-binding protein, suggesting that neuronal degeneration in polyglutamine diseases may result from nuclear depletion of transcription factors containing the glutamine-rich domain. It was also revealed that, in the DRPLA brain, expanded polyglutamine stretches were diffusely accumulated in neuronal nucleoplasm. This nuclear pathology involved many neurons in various nervous system regions, such as the cerebral cortex, thalamus, substantia nigra, pontine nuclei, reticular formation and inferior olive, in addition to the previously recognized affected regions. The diffuse nuclear labeling was also detected in MJD, Huntington's disease, and spinal and bulbar muscular atrophy, suggesting that this nuclear pathology may be a characteristic feature and may exert certain influence on certain nuclear functions of many neurons in the CAG repeat diseases.

The carboxy-terminal fragment of α1A calcium channel preferentially aggregates in the cytoplasm of human spinocerebellar ataxia type 6 Purkinje cells

“…7c, arrow ). Diffuse labeling of the nucleus, as described in DRPLA, MJD, and other polyQ diseases [63], was never observed. The nuclei of Purkinje cells were not obviously stained as in controls.…”

“…Finally, an increase in nuclear CTF localization may affect normal nuclear function, considering the previous work expressing the CTF resulted in cell death [22]. Although SCA6 do not show prominent intranuclear aggregates or diffuse nuclear staining described in other polyQ diseases [63], it is possible to consider that SCA6 conforms to other polyQ diseases in that soluble polyQ-containing protein exists in the nucleus. A line of evidence suggests that nuclear inclusions in other polyQ diseases may even act to protect neurons from polyQ-mediated toxicity [54], while a soluble monomer or oligomers of expanded polyQ-containing proteins are more toxic to cells [31, 46].…”

Coexistence of Huntington’s disease and amyotrophic lateral sclerosis: a clinicopathologic study

“…Both showed obvious upper and lower motor neuron loss with Bunina bodies and ubiquitin-ir skein-like inclusions in remaining lower motor neurons, which are characteristic of ALS [15, 28], as well as neuronal loss and gliosis in the neostriatum together with polyglutamine inclusion-containing neurons, which are hallmarks of HD [9, 11, 43]. A single reported autopsy case with HD and familial ALS likewise had these characteristics of ALS and HD, but also showed degeneration of posterior columns and dorsal spinocerebellar tracts, which was not present in our cases [31].…”

Peripheral Neuropathy of Machado-Joseph Disease in Taiwan: A Morphometric and Genetic Study

“…Neuronal intranuclear polyglutamine inclusions have become the neuropathological signature of the CAG repeat disease, although their cytotoxicity is a matter of controversy [20]. No animal model is currently available for the detailed analysis of the underlying mechanisms.…”