BackgroundAlpha-synuclein (SNCA) gene expression is an important factor in the pathogenesis of Parkinson's disease (PD). Gene multiplication can cause inherited PD, and promoter polymorphisms that increase SNCA expression are associated with sporadic PD. CpG methylation in the promoter region may also influence SNCA expression.Methodology/Principal FindingsBy using cultured cells, we identified a region of the SNCA CpG island in which the methylation status altered along with increased SNCA expression. Postmortem brain analysis revealed regional non-specific methylation differences in this CpG region in the anterior cingulate and putamen among controls and PD; however, in the substantia nigra of PD, methylation was significantly decreased.Conclusions/SignificanceThis CpG region may function as an intronic regulatory element for SNCA gene. Our findings suggest that a novel epigenetic regulatory mechanism controlling SNCA expression influences PD pathogenesis.

Our results strongly confirm that ITPR1 is the causative gene for SCA15 and suggest that we need to investigate the point mutation in ITPR1 in the patients with autosomal dominant cerebellar ataxia and tremor.

Hypersomnia occurs frequently in patients with myotonic dystrophy (MyD). We performed a quantitative immunohistochemical study of serotonin (5-HT)-containing neurons linked to hypersomnia in the dorsal raphe nucleus (DRN) and the superior central nucleus (SCN) in 8 patients with MyD, 5 of whom showed hypersomnia, and in 12 age-matched controls. The densities of 5-HT neurons in the DRN and the SCN were significantly lower in MyD patients with hypersomnia than in MyD patients without hypersomnia and controls. These data suggest that the loss of 5-HT neurons of the DRN and the SCN is associated with the presence of hypersomnia in MyD.

Three autosomal dominant spinocerebellar ataxias, dentatorubral-pallidoluysian atrophy (DRPLA), Machado-Joseph disease (MJD), and spinocerebellar ataxia type 1 (SCA1), are associated with the expansion of a CAG repeat in the respective genes. To investigate the association between CAG repeat expansion and neuropathological findings, we analyzed several brain regions from 9 cases of DRPLA, 3 cases of MJD, and 1 case of SCA1. We found that the expanded alleles were smaller in the cerebellar cortex than in other brain regions, such as the frontal cortex, in these three diseases. The discrepancy in the expanded CAG repeat length between cerebellar cortex and other tissues was most prominent in DRPLA, and especially in cases of adult-onset DRPLA. A significant correlation was found between the age at onset of DRPLA and the size of the CAG repeat expansion. Cerebella of DRPLA patients were microscopically dissected into three layers, the molecular and granular layers and the white matter, which were analyzed separately. The lower level of CAG repeat expansion in DRPLA cerebella was representative of CAG repeat expansion in the granule cells. The microdissected samples of the granular layer of the hippocampal formation, which is densely packed with neuronal cells, revealed that the degree of CAG repeat expansion in this layer was similar to that in the cerebellum. These observations suggest that granule cells in the cerebellum and hippocampus have low levels of CAG repeat expansion, and that other types of cells exhibit a higher level of CAG repeat expansion, in spinocerebellar ataxias.

Respiratory insufficiency occurs frequently in patients with myotonic dystrophy (MyD). We have performed a quantitative study of neurons linked to respiratory function in the dorsal central medullary nucleus (DCMN), the ventral central medullary nucleus (VCMN), and the subtrigeminal medullary nucleus (SMN) in seven patients with MyD and eight age-matched controls. Alveolar hypoventilation of the central type occurred in three of the MyD patients but not in the remaining MyD patients or controls. The densities of neurons of the DCMN, the VCMN, and the SMN in MyD patients with hypoventilation were significantly lower than in MyD without hypoventilation and controls. These data suggest the neuronal loss of the DCMN, VCMN, and SMN is associated with the presence of hypoventilation in MyD and may be an important feature of MyD.