Alpha-synuclein (SNCA) is a major risk gene for Parkinson's disease (PD), and increased SNCA gene dosage results in a parkinsonian syndrome in affected families. We found that methylation of human SNCA intron 1 decreased gene expression, while inhibition of DNA methylation activated SNCA expression. Methylation of SNCA intron 1 was reduced in DNA from sporadic PD patients' substantia nigra, putamen, and cortex, pointing toward a yet unappreciated epigenetic regulation of SNCA expression in PD.
Multiple lines of evidence suggest a link between environmental toxins and Parkinson's disease (PD). Although numerous studies reported associations of genetic variants in de-toxifying enzymes, i.e. cytochrome genes, with PD. Epigenetic modifications of genes and subsequent altered expression may confer a yet unappreciated level of susceptibility. We present a genome-wide methylation analysis of PD with quantitative DNA methylation levels of 27.500 CpG sites representing 14.495 genes. We found decreased methylation of the cytochrome P450 2E1 gene and increased expression of CYP2E1 messenger RNA in PD patients' brains, suggesting that epigenetic variants of this cytochrome contribute to PD susceptibility.
Although ataxia is by definition the prominent symptom of ataxia disorders, there are various neurological signs that may accompany ataxia in affected patients. Reliable and quantitative assessment of these signs is important because they contribute to disability, but may also interfere with ataxia. Therefore we devised the Inventory of Non-Ataxia Signs (INAS), a list of neurological signs that allows determining the presence and severity of non-ataxia signs in a standardized way. INAS underwent a rigorous validation procedure that involved a trial of 140 patients with spinocerebellar ataxia (SCA) for testing of inter-rater reliability and another trial of 28 SCA patients to assess short-term intra-rater reliability. In addition, data of the ongoing EUROSCA natural history study were used to determine the reproducibility, responsiveness and validity of INAS. Inter-rater reliability and short-term test-retest reliability was high, both for the total count and for most of the items. However, measures of responsiveness, such as the smallest detectable change and the clinically important change were not satisfactory. In addition, INAS did not differentiate between subjects that were subjectively stable and those that worsened in the 2-year observation period. In summary, INAS and INAS count showed good reproducibility, but unsatisfactory responsiveness. The present analysis and published data from the EUROSCA natural history study suggest that INAS is a valid measure of extracerebellar involvement in progressive ataxia disorders. As such, it is useful as a supplement to the measures of ataxia, but not as a primary outcome measure in future interventional trials.
α-Synuclein methylation levels depended on disease status, sex, age, and the genotype of rs3756063. The pharmacological action of L-dopa was not limited to the dopamine precursor function but included epigenetic off-target effects. The hypomethylation of α-synuclein in sporadic PD patients' blood already observed in previous studies was probably underestimated because of effect of L-dopa, which was not known previously. The analysis of α-synuclein methylation can help to identify nonparkinsonian individuals with reasonable specificity, which offers a valuable tool for researchers and clinicians.
Epigenetic processes control the embryonic development into multicellular organisms and determine the functional differences of genetically identical cells and individuals. They are also involved in a variety of complex functions such as learning and memory consolidation and have been implicated in aging processes. Beyond the actual genetic information encoded in the DNA sequence, epigenetic modifications in particular DNA methylation and various histone modifications shape the chromatin into a transcriptional permissive or repressive state. DNA methylation patterns are altered by environmental conditions and can be carried forward through mitosis and meiosis. Hence, DNA methylation probably mediates complex environment-gene interactions, determines individual disease characteristics, and contributes to effects and side effects of drugs. In addition to classic monogenic epigenetic diseases, i.e., Prader-Willi and Rett syndrome, recent data point to an epigenetic component also in apparent sporadic neuro-psychiatric disorders and increasing evidence suggests a role for altered DNA methylation in Parkinson's disease. Epigenetic alterations, DNA methylation in particular, may account for the yet unexplained individual susceptibility and the variability in the course of Parkinson's disease and could provide hints toward the development of novel therapeutic targets.
Whole body vibration (WBV) is a biomechanical treatment used widely in professional sports and rehabilitation. We examined the effect of stochastic WBV on ataxia in spinocerebellar ataxia types 1, 2, 3, and 6 (SCA 1, 2, 3 and 6) in a single-center double-blind sham-controlled study. Stochastic WBV was applied on four sequent days, each treatment consisting of five stimulus trains of 60-s duration at a frequency of 6.5 Hz and 60-s resting time between stimuli (n = 17). Patients allocated to the sham group received the same treatment with 1 Hz (n = 15). All patients were rated at baseline and after the last treatment using clinical scores (SARA, SCAFI, and INAS). After treatment, we found significant improvements of gait, posture, and speed of speech in the verum group while limb kinetics and ataxia of speech did not respond. Stochastic WBV might act on proprioceptive mechanisms and could also stimulate non-cerebellar/compensatory mechanisms. But at present, the involved cellular mechanism and the presumed neuronal loops cannot be deciphered. Thus, future work is needed to understand the mechanisms of whole body vibration. Finally, the use of stochastic WBV could provide a supplementation to treat ataxia in SCA and can be combined with physiotherapeutical motor training.
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