Epigenetic Analysis in Human Neurons: Considerations for Disease Modeling in PD

Parkinson’s disease (PD) is the second most common neurodegenerative disorder next to Alzheimer’s disease. Most PD cases are considered to be sporadic and despite considerable scientific effort, the underlying cause(s) still remain(s) enigmatic. In particular, it is unknown to which extent epigenetic alterations contribute to the pathophysiology of this devastating disorder. This is partly due to the fact that appropriate PD models are not yet available. Moreover, epigenetic patterns and mechanisms are species specific and murine systems reflect only a few of the idiosyncrasies of human neurons. For several years now, patient-specific stem cell-derived neural and non-neural cells have been employed to overcome this limitation allowing the analysis and establishment of humanized disease models for PD. Thus, several studies tried to dissect epigenetic alterations such as aberrant DNA methylation or microRNA patterns using lund human mesencephalic cell lines or neurons derived from (patient-specific) induced pluripotent stem cells. These studies demonstrate that human neurons have the potential to be used as model systems for the study of epigenetic modifications in PD such as characterizing epigenetic changes, correlating epigenetic changes to gene expression alterations and hopefully using these insights for the development of novel therapeutics. However, more research is required to define the epigenetic (age-associated) landscape of human in vitro neurons and compare these to native neurons before they can be established as suitable models for epigenetic studies in PD. In this review, we summarize the knowledge about epigenetic studies performed on human neuronal PD models, and we discuss advantages and current limitations of these (stem cell-derived) neuronal models for the study of epigenetic alterations in PD

Bell's palsy: combined treatment of famciclovir and prednisone is superior to prednisone alone

There is insufficient evidence concerning the efficacy of antiviral treatment of Bell's palsy (BP). We therefore compared the efficacy of prednisone and famciclovir to prednisone treatment alone in BP. A total of 167 consecutive patients with untreated acute BP were included. Severity of BP was evaluated using the House-Brackmann scale (HBS) and virus antibody tests (herpes simplex virus, varicella zoster virus) were performed. Patients admitted on even dates were treated with prednisone ("P group") and patients admitted on odd dates were treated with prednisone and famciclovir ("P+F group"). 117 patients completed the follow-up after 3 months or later (67 P/51 P+F). While most patients showed at least partial recovery with both treatment types, improvement of at least 4 grades in the HBS was more common in the "P+F group" (29.4 % vs. 11.9 %), whereas smaller changes of less than 3 grades were more common in the "P group" (29.9 % vs. 17.6 %; Chi-square test, p = 0.02). Patients with complete BP (HBS grade of 5 or 6) had significantly better chances of reaching normal function if treated with famciclovir additionally instead with prednisone alone (73.7 % vs. 47.1 %; Cochran-Armitage trend test, p = 0.03). These results suggest that the combined treatment of famciclovir and prednisolone should be considered (at least) in patients with severe BP

Potassium channel dysfunction and depolarized resting membrane potential in a cell model of SCA3

Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant inherited neurodegenerative disease caused by the expansion of a polyglutamine repeat within the disease protein, ataxin-3. There is growing evidence that neuronal electrophysiological properties are altered in a variety of polyglutamine diseases such as Huntington's disease and SCA1 and that these alterations may contribute to disturbances of neuronal function prior to neurodegeneration. To elucidate possible electrophysiological changes in SCA3, we generated a stable PC12 cell model with inducible expression of normal and mutant human full-length ataxin-3 and analyzed the electrophysiological properties after induction of the recombinant ataxin-3 expression. Neuronally differentiated PC12 cells expressing the expanded form of ataxin-3 showed significantly decreased viabilities and developed ultrastructural changes resembling human SCA3. Prior to neuronal cell death, we found a significant reduction of the resting membrane potential and a hyperpolarizing shift of the activation curve of the delayed rectifier potassium current. These findings indicate that electrophysiological properties are altered in mutant ataxin-3 expressing neuronal cells and may contribute to neuronal dysfunction in SCA3