Parkin promotes degradation of the mitochondrial pro-apoptotic ARTS protein.

Parkinson's disease (PD) is associated with excessive cell death causing selective loss of dopaminergic neurons. Dysfunction of the Ubiquitin Proteasome System (UPS) is associated with the pathophysiology of PD. Mutations in Parkin which impair its E3-ligase activity play a major role in the pathogenesis of inherited PD. ARTS (Sept4_i2) is a mitochondrial protein, which initiates caspase activation upstream of cytochrome c release in the mitochondrial apoptotic pathway. Here we show that Parkin serves as an E3-ubiquitin ligase to restrict the levels of ARTS through UPS-mediated degradation. Though Parkin binds equally to ARTS and Sept4_i1 (H5/PNUTL2), the non-apoptotic splice variant of Sept4, Parkin ubiquitinates and degrades only ARTS. Thus, the effect of Parkin on ARTS is specific and probably related to its pro-apoptotic function. High levels of ARTS are sufficient to promote apoptosis in cultured neuronal cells, and rat brains treated with 6-OHDA reveal high levels of ARTS. However, over-expression of Parkin can protect cells from ARTS-induced apoptosis. Furthermore, Parkin loss-of-function experiments reveal that reduction of Parkin causes increased levels of ARTS and apoptosis. We propose that in brain cells in which the E3-ligase activity of Parkin is compromised, ARTS levels increase and facilitate apoptosis. Thus, ARTS is a novel substrate of Parkin. These observations link Parkin directly to a pro-apoptotic protein and reveal a novel connection between Parkin, apoptosis, and PD.

Entropy values of intellectually-disabled and normal children undergoing deep intravenous sedation for dental treatment.

BACKGROUND: Intravenous sedation is an efficient method to facilitate dental treatment delivery to uncooperative children. Entropy is used for monitoring anesthetic depth. Nonetheless, scarce data is found on entropy monitoring in intellectually-disabled patients during sedation. OBJECTIVE: This comparative study set out to evaluate entropy values of normal and intellectually-disabled patients during the steady state period of deep sedation and awakening. Additionally, the study aimed to establish whether normal and intellectually-disabled patients reached a comparable clinically assessed state of sedation and the doses of total anesthetic drugs administered. MATERIALS AND METHODS: 30 patients were included in the study and divided into two groups: 16 normal and 14 intellectually-disabled children. Ages ranged between 2 to 16 years. All patients were assigned to receive dental treatment under intravenous sedation. Entropy tracings were recorded for all patients. Clinical sedation level was assessed every 5 minutes. Drug administration was guided clinically. The anesthesiologist was blinded to entropy tracing. RESULTS: Although sedation levels assessed clinically were similar between groups, entropy values were significantly lower in the group of intellectually-disabled patients both during sedation steady state and waking. The total amount of anesthetic drugs administered to normal patients was higher compared to intellectually-disabled patients. CONCLUSION: In this study, entropy monitoring was found to be a more sensitive modality for assessing intra-operative brain activity during steady state sedation compared to clinical assessment of sedation. Despite similar clinical assessment of sedation level, brain activity was lower in the intellectually-disabled group as were their anesthetic drug requirements. We conclude that intellectually-disabled patients may need less anesthetic drugs to reach a good level of sedation. Whether the lower level of brain activity during sedation, reflected by lower entropy tracings, is characteristic of the intellectually disabled warrants additional studies.