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.

Huntington disease and its related autosomal-dominant polyglutamine (pQ) neurodegenerative diseases are characterized by intraneuronal accumulation of protein aggregates. Studies on protein aggregates have revealed the importance of the ubiquitin-proteasome system as the front line of protein quality control (PQC) machinery against aberrant proteins. Recently, we have shown that the autophagy-lysosomal system is also involved in cytoplasmic aggregate degradation, but the nucleus lacked this activity. Consequently, the nucleus relies entirely on the ubiquitin-proteasome system for PQC. According to previous studies, nuclear aggregates possess a higher cellular toxicity than do their cytoplasmic counterparts, however degradation kinetics of nuclear aggregates have been poorly understood. Here we show that nuclear ubiquitin ligases San1p and UHRF-2 each enhance nuclear pQ aggregate degradation and rescued pQ-induced cytotoxicity in cultured cells and primary neurons. Moreover, UHRF-2 is associated with nuclear inclusion bodies in vitro and in vivo. Our data suggest that UHRF-2 is an essential molecule for nuclear pQ degradation as a component of nuclear PQC machinery in mammalian cells. Huntington disease (HD)2 and related polyglutamine (pQ) diseases are caused by the expansion of trinucleotide repeats encoding pQ within the mutant gene product (1). The pQ length dependence of disease onset and severity in pQ diseases correlates strongly with the tendency of expanded pQ proteins to aggregate in disease models (2, 3). Because of this pQ chain, the gene product assembles into oligomers, further aggregates to form microscopically visible inclusion bodies (IBs), and shows pathological extensity in diseased brains (4).Aggregated forms of pQ-expanded huntingtin (Htt) can disrupt cellular function in a variety of ways, including inactivation of transcription factors (5, 6) and impairment of the ubiquitin proteasome system (UPS) (7). The precise mechanism of UPS inhibition remains to be solved, but could be of particular interest, because it has been shown to occur in in vivo disease models (8). UPS impairment triggers aggresome formation (9), an active cellular mechanism to enrich cytoplasmic aggregates and autophagy-lysosomal components to the microtubule-organizing center by retrograde transport, which in turn enhances the efficiency and selectivity of autophagic degradation of cytoplasmic aggregates supporting the UPS as an alternative protein quality control (PQC) system (10, 11). However, autophagy is ineffective in clearing nuclear aggregates (12), and there is no known nuclear PQC mechanism other than the UPS. Therefore, the nucleus is a relatively protected environment for aggregates than the cytoplasm.The majority of the pQ proteins are functional in the nucleus, and the strong correlation between aggregate toxicity and nuclear translocation of pQ proteins has led to the hypothesis that the nucleus is the primary center for action of these proteotoxins (13). This was shown by redirecting nuclear ataxin-1 or andro...

We report a 40-year-old man with severe hypokinesis as paraneoplastic manifestation of a microscopic "carcinoma in situ" of the testis. The young age of the patient, along with progressive neurologic deterioration, detection of anti-Ma2 antibodies, and ultrasound findings of bilateral microcalcifications, led to bilateral orchiectomy, revealing the tumor in both testes. After orchiectomy, neurological symptoms stabilized, but the patient eventually died of systemic complications caused by his severe neurological deficits. Anti-Ma2 paraneoplastic encephalitis should be considered in patients with severe hypokinesis, and intensive investigation and aggressive approach to treatment is encouraged to prevent progression of the neurological deficits. Keywordsanti-Ma2 paraneoplastic encephalitis; hypokinesis; Parkinsonism; intratubular germ-cell neoplasia Paraneoplastic anti-Ma2-associated encephalitis usually results in limbic, diencephalic, and brainstem dysfunction. Predominant hypokinesis, however, has been rarely reported. 1 We report a patient with this disorder who developed severe hypokinesis as predominant clinical features, and whose underlying neoplasm was a microscopic "carcinoma in situ" of the testis. CASE REPORTSA 40-year-old Japanese man developed diplopia and unsteadiness of gait in July 2004. Within the next 2 months he developed progressive difficulty in moving his extremities, and by the middle of August, he could not get out from bed. His facial expression became markedly reduced and the voice barely audible. He also developed severe micrographia. The patient was initially seen by a psychiatrist who prescribed antidepressants, without significant improvement of symptoms. By the end of August, he had difficulty in swallowing, and tremor when holding objects. He looked anxious, irritable, and became very sensitive to auditory stimuli. In September, the patient was seen at a local hospital and found to have reduced

Subclinical carotid atherosclerosis, defined as thickened IMT, could be a marker for early stages of CI, especially for immediate memory recall. The impairment is presumably caused by inducing cerebral microvascular dysfunction in the frontal lobe. Geriatr Gerontol Int 2018; 18: 65-71.

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