Cerebellar degeneration in hereditary dentatorubral-pallidoluysian atrophyand Machado-Joseph disease

We examined the mechanism of cerebellar degeneration in brains obtained at autopsy from six cases of hereditary dentatorubral-pallidoluysian atrophy ( DRPLA) and six cases of Machado-Joseph disease (MJD), using terminal deoxyn ucleotidyltransferase-mediated in situ nick end labeling (TUNEL) and immuno histochemistry for apoptosis-related proteins, neurotrophin recep- tors and glutamate transporters. In three subjects with DRPLA who developed dementi a and cerebellar ataxia at over 50 years of age, the number of Purkinje cel ls was mildly reduced, TUNEL-positive cells were observed in the molecular layer of the cerebellar cortex, and immunoreactivities for calbindin D28K a nd excitatory amino acid transporter-1 (EAAT1) were altered in the molecula r layer. In addition, all cases of DRPLA showed a reduction of immunoreacti vity for EAAT1 in the dentate nucleus. In MJD, augmentation of Bcl-x expres sion by the Purkinje cells, and increases in Trk B- and GFAP-immunopositive glial cells in the granular layer were observed in half of the cases, wher eas immunoreactivity for EAAT-1 was preserved both in the cerebellar cortex and dentate nucleus. One case of MJD showed TUNEL-positive granular cells in the cerebellar cortex. Age-matched control subjects did not show TUNEL-p ositive cells or immunohistochemical changes in the cerebellum. There were neither TUNEL-positive cells nor alteration of the in situ expression of ap optosis-related proteins in the dentate nucleus in either variant of heredi tary spinocerebellar degeneration, although both exhibited grumose degenera tion in the dentate nucleus. These findings indicate that latent degenerati on in the cerebellar cortex may occur in DRPLA and MJD, in addition to the dentate change, which is the cardinal feature in the neuropathology of thes e two diseases. The lesion of Purkinje cells and their processes in the mol ecular layer associated with altered glutamate transport may be important i n DRPLA, while the significance of the abnormalities observed in some MJD c ases, which might be related to apoptotic mechanism, remains unclear.