Wei, Jianning

Kleine-Levin Syndrome (KLS) is an extremely rare neurological disorder characterized by episodes of uncontrollable hypersomnia and various cognitive and behavioral abnormalities. There is neither a definitive etiology nor definite treatment modalities. Immunological studies for this condition are extremely limited, and this present study aims to investigate a potential autoimmune mechanism that underlies KLS. To achieve this, western blot and dot-blot assays analyzed the immunoreactivity of patients and control sera towards various brain tissue areas. Western blot did not show immunoreactivity with IgG-depleted brain tissue lysate. However, dot-blot assays revealed a significantly greater level of immunoreactivity with KLS patient sera towards the dorsolateral prefrontal cortex, hypothalamus, and parieto-temporal areas compared to KLS-negative sera. These areas have previously been shown to be hypo-perfused in KLS patients. Future studies are necessary to identify the specific antibodies that may be autoreactive in KLS patients.

Chapter 1: Background: The search for effective electric stimulation protocols for peripheral nerve regeneration, specifically in dorsal root ganglion (DRG), is an ongoing area of interest. Multiple stimulation parameters using direct current, alternating current and pulsed magnetic electric fields have proven to increase neurite regeneration. In the past, there has been limited exploration of the impact of action potential-like electrical stimulation on DRG regeneration. New method: A novel action potential-like electrical stimuli output from a custom-built action potential generator board was used to assess multiple stimulation parameters on DRG regeneration. Finite-element modeling was used to determine electrolyte potential across a non-uniform electric field to test the effects of electric field strength from action potential-like stimuli on DRG regeneration. Total neurite length and neurite branching per DRG were examined for each applied field strength and frequency to determine the effects of action potential-like stimulation on DRG structural regeneration. Results: Action potential-like stimulation showed inhomogeneous distribution of neurite regeneration and branching with higher regeneration and branching seen in areas away from the electrodes compared to the nearly homogenous distribution seen from the controls. Whole well analysis showed significant increases in total neurite regeneration and branching across all stimulation conditions with electric field strength, particularly 40 V/m, having the strongest effect on DRG structural regeneration. Comparison with existing methods: This study provides preliminary evidence supporting the hypothesis that action potential-like electric fields can improve DRG regeneration. Conclusions: This system and method may have applications for clinical interventions aimed at rehabilitating damaged peripheral nerve pathways.

Huntington's disease (HD) is an inherited neurological disorder characterized by a
selective loss of neurons in the striatum and cortex leading to involuntary movement,
dementia and eventually cell death. HD is caused by an expanded polyglutamine (PolyQ)
repeat in Huntingtin (Htt) protein. It is well known that misfolded mutant Htt could form
intracellular aggregates, trigger ER stress and ultimately lead to apoptosis. However, the
molecular link between ER stress and apoptosis in mitochondria is poorly understood. In
the present study, we identified Bim (Bcl-2 interacting mediator of cell death) as the
essential protein. We first established a cellular model of HD by over expressing the Nterminus
of wild type and mutant Htt into HEK293 cell lines. We showed that the
accumulation and aggregation of misfolded mutant Htt protein triggers ER stress and
apoptosis. The Bim protein expression level was greatly increased in mutant Htt
transfected cells and this increase was partially due to up-regulation of Bim mRNA as analyzed using quantitative RT-PCR. We further showed that Bim phosphorylation
also played an important role in regulating Bim expression. Moreover, up-regulation of
Bim facilitates the translocation of Bax to mitochondrial membrane, which lead to
cytochrome c release and apoptosis. We also silenced Bim using siRNA to further
investigate the essential role of Bim in mutant Htt induced ER stress and apoptosis.
Identifying the Bim pathway that is altered in response to the mutant Htt protein is
important for understanding the cellular processes impacted by the disease.