CNS Changes in DRPLA with Dementia and Personality Changes: CT, MR and SPECT Findings

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 (TAFII130), 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.

Section: Diffuse Intranuclear Accumulation Of Expanded Polyglutamine mentioning

confidence: 97%

Pathology of CAG repeat diseases

Yamada¹,

Tsuji

Takahashi³

2000

“…The extensive involvement of multiple brain regions may be responsible for a variety of clinical features and electroencephalogram abnormalities in DRPLA patients. [42][43][44][45][46][47] Diffuse nuclear labeling, with apparent staining of occasional intranuclear inclusions, was also detectable in some glial cells in various CNS regions including the white matter.…”

Section: Diffuse Intranuclear Accumulation Of Expanded Polyglutamine mentioning

confidence: 99%

Pathology of CAG repeat diseases

Yamada¹,

Tsuji²,

Takahashi³

2000

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 involvement of the dentatorubral and pallidoluysian systems in the first group suggests a close relationship between the nuclear pathology and neuronal degeneration in DRPLA; however, the additional involvement of the regions that show a preservation of neuronal population in this group, such as the pontine nuclei, indicates that neuronal cell death is not regulated by the polyglutamine pathology alone. The results also indicate that the novel lesion distribution is not static, but quite variable depending on the CAG‐repeat sizes, and that the dynamic polyglutamine pathology might be responsible for a variety of clinical features and EEG abnormalities in DRPLA patients 29–34 . It is likely that in DRPLA, neuronal cell death represents only a part of the pathological changes and that the prevalent and variable accumulation of mutant proteins in neuronal nuclei is an essential neuropathology that plays a pivotal role in the development of the clinical manifestations of the disease.…”

Section: Novel Neuropathology Related To Polyglutamine Expansionmentioning

confidence: 87%

“…The results also indicate that the novel lesion distribution is not static, but quite variable depending on the CAG-repeat sizes, and that the dynamic polyglutamine pathology might be responsible for a variety of clinical features and EEG abnormalities in DRPLA patients. [29][30][31][32][33][34] It is likely that in DRPLA, neuronal cell death represents only a part of the pathological changes and that the prevalent and variable accumulation of mutant proteins in neuronal nuclei is an essential neuropathology that plays a pivotal role in the development of the clinical manifestations of the disease.…”

Section: Novel Neuropathology Related To Polyglutamine Expansionmentioning

confidence: 99%

Polyglutamine disease: Recent advances in the neuropathology of dentatorubral‐pallidoluysian atrophy

Yamada¹,

Shimohata

Sato

et al. 2006

Polyglutamine diseases are hereditary neurodegenerative disorders that are caused by the expansion of a CAG repeat in the causative genes. They comprise at least nine disorders, including DRPLA, HD, and Machado-Joseph disease. Initially, the discovery of neuronal intranuclear inclusions (NIIs) in human brains and in a murine model of HD provided a plausible hypothesis that the expression of expanded polyglutamine stretches leads to NII formation, resulting in neuronal cell death in selective brain regions characteristic to each disease. Recent studies, however, suggest that nuclear dysfunction, especially transcriptional abnormalities caused by the diffuse intranuclear accumulation of mutant proteins, plays a pivotal role in the development and progression of clinical symptoms. Polyglutamine diseases have a similarity with neuronal storage disease, and this pathological process might become a target for the establishment of an effective therapy for these diseases.