[Formation of neuronal inclusions and neurodegeneration: with special reference to dentatorubral-pallidoluysian atrophy].
A new entity--the conformational disease--an otherwise diverse group of disorders, includes several currently incurable brain diseases such as Alzheimer's disease, prion encephalopathies and inherited polyglutamine diseases (PGDs) in which it is proposed that conformational changes in certain proteins and their subsequent aggregation represent the common pathogenic mechanism of neurodegeneration. In several PGDs including dentatorubral-pallidoluysian atrophy (DRPLA), neuronal intranuclear inclusions (NIIs) have been identified. Here I describe our recent studies on DRPLA. Formation of both intranuclear and intracytoplasmic inclusions by mutant DRPLA proteins with an expanded polyglutamine stretch was demonstrated in an in vitro experiment. Inclusion-containing non-brain cells were found to undergo apoptosis. In human DRPLA, similar intranuclear inclusions were detected in neurons in various brain regions. However, intracytoplasmic inclusions were found exclusively in neurons in the cerebeller dentate nucleus. The pontine nuclei neurons with NIIs, for instance, appeared to be small (atrophic), but healthy. The question of whether these NIIs actually kill brain cells in the human disease, remains unclear. Recently, NIIs were studied immunohistochemically using antibodies against transcription factors, and were found to contain TAFIIp130, Sp 1 and CREB-1. These results are of great interest when considering not only how the neurodegenerative mechanism progresses but also why the inclusions are located in nuclei in PGDs. Finally, Tsuji and colleagues recently established a transgenic mouse model of DRPLA. In these mice, NIIs, which were identical to those seen in the human disease, were confirmed in various brain regions. Further detailed studies of this model will contribute to a better understanding of the formation of neuronal inclusions and neurodegeneration in DRPLA.
Takahashi
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Department of Pathology, Niigata University.
D000818:Animals; D001921:Brain / Q000473:pathology*; D006801:Humans; D002479:Inclusion Bodies / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D020191:Myoclonic Epilepsies, Progressive / Q000473:pathology*