Precise control of mitophagy through ubiquitin proteasome system and deubiquitin proteases and their dysfunction in Parkinson's disease.

Parkinson's disease (PD) is one of the most common neurodegenerative diseases in the elderly population and is caused by the loss of dopaminergic neurons. PD has been predominantly attributed to mitochondrial dysfunction. The structural alteration of α-synuclein triggers toxic oligomer formation in the neurons, which greatly contributes to PD. In this article, we discuss the role of several familial PD-related proteins, such as α-synuclein, DJ-1, LRRK2, PINK1, and parkin in mitophagy, which entails a selective degradation of mitochondria via autophagy. Defective changes in mitochondrial dynamics and their biochemical and functional interaction induce the formation of toxic α-synucleincontaining protein aggregates in PD. In addition, these gene products play an essential role in ubiquitin proteasome system (UPS)-mediated proteolysis as well as mitophagy. Interestingly, a few deubiquitinating enzymes (DUBs) additionally modulate these two pathways negatively or positively. Based on these findings, we summarize the close relationship between several DUBs and the precise modulation of mitophagy. For example, the USP8, USP10, and USP15, among many DUBs are reported to specifically regulate the K48- or K63-linked de-ubiquitination reactions of several target proteins associated with the mitophagic process, in turn upregulating the mitophagy and protecting neuronal cells from α-synuclein-derived toxicity. In contrast, USP30 inhibits mitophagy by opposing parkin-mediated ubiquitination of target proteins. Furthermore, the association between these changes and PD pathogenesis will be discussed. Taken together, although the functional roles of several PD-related genes have yet to be fully understood, they are substantially associated with mitochondrial quality control as well as UPS. Therefore, a better understanding of their relationship provides valuable therapeutic clues for appropriate management strategies. [BMB Reports 2021; 54(12): 592-600].

Light-Mediated Inhibition of Colonic Smooth Muscle Constriction and Colonic Motility via Opsin 3.

Opsin photoreceptors outside of the central nervous system have been shown to mediate smooth muscle photorelaxation in several organs. We hypothesized that opsin receptor activation in the colon would have a similar effect and influence colonic motility. We detected Opsin 3 (OPN3) protein expression in the colonic wall and demonstrated that OPN3 was present in enteric neurons in the muscularis propria of the murine colon. Precontracted murine colon segments demonstrated blue light (BL) -mediated relaxation ex vivo. This photorelaxation was wavelength specific and was increased with the administration of the chromophore 9-cis retinal and a G protein receptor kinase 2 (GRK2) inhibitor. Light-mediated relaxation of the colon was not inhibited by L-NAME or tetrodotoxin (TTX). Furthermore, BL exposure in the presence of 9-cis retinal decreased the frequency of colonic migrating motor complexes (CMMC) in spontaneously contracting mouse colons ex vivo. These results demonstrate for the first time a receptor-mediated photorelaxation of colonic smooth muscle and implicate opsins as possible new targets in the treatment of spasmodic gastrointestinal dysmotility.

Tympanometry and CT Measurement of Middle Ear Volumes in Patients with Unilateral Chronic Otitis Media.

OBJECTIVES: The goals of the study were to compare the middle ear (ME) volumes from both normal and lesioned ears, and these ME volumes were measured by a digital image processing computed tomography (CT) program in patients with unilateral chronic otitis media, and we wanted to compare the ME volumes of the lesioned ears by comparing the ME volumes obtained by tympanometry with those ME volumes measured by the digital image processing CT program. METHODS: Forty-four patients who had unilateral chronic otitis media (COM) and contralateral normal tympanic membranes (TM) and 100 subjects with normal TMs were included in the study. The normal volumes of the external auditory canal (EAC) were measured in the normal group. The tympanometric ME volumes in the ears with a perforated TM were calculated as the difference of the tympanometric volumes measured from the both ears in patients with unilateral COM. The CT ME volumes were measured by a digital image processing program. RESULTS: The tympanometric volumes of the EACs in the ears with normal TMs were 1.4+/-0.3 mL. There were no significant differences according to gender, age and the side of the face the ear was on. The tympanometric volumes of the EAC in the normal-side ear of the patients with unilateral COM showed no significant differences when compared with those from the normal group. The ME volumes of the intact ears, as measured by CT, showed significantly higher values than those ME volumes of the lesioned ears. The ME volumes of the lesioned ears, as measured by tympanometry, showed a strong, significant linear correlation with those ME volumes calculated by CT; however, the ME volumes of the lesioned ears, as measured by tympanometry (1.5+/-1.4 mL), were significantly larger than those ME volumes measured by CT (1.1+/-0.8 mL). CONCLUSION: Our results show that chronic otitis media causes reduced ME volumes compared to those ME volumes of the contralateral normal ears. Tympanometry can provide a valuable estimation of the ME volumes in chronic ears, although it tends to overestimate the ME volumes, and especially for the ears with a larger ME volume.