The Wolfram-like variant WFS1E864K destabilizes MAM and compromises autophagy and mitophagy in human and mice.

Dominant variants in WFS1 (wolframin ER transmembrane glycoprotein), the gene coding for a mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) resident protein, have been associated with Wolfram-like syndrome (WLS). In vitro and in vivo, WFS1 loss results in reduced ER to mitochondria calcium (Ca2+) transfer, mitochondrial dysfunction, and enhanced macroautophagy/autophagy and mitophagy. However, in the WLS pathological context, whether the mutant protein triggers the same cellular processes is unknown. Here, we show that in human fibroblasts and murine neuronal cultures the WLS protein WFS1E864K leads to decreases in mitochondria bioenergetics and Ca2+ uptake, deregulation of the mitochondrial quality system mechanisms, and alteration of the autophagic flux. Moreover, in the Wfs1E864K mouse, these alterations are concomitant with a decrease of MAM number. These findings reveal pathophysiological similarities between WS and WLS, highlighting the importance of WFS1 for MAM's integrity and functionality. It may open new treatment perspectives for patients with WLS.Abbreviations: BafA1: bafilomycin A1; ER: endoplasmic reticulum; HSPA9/GRP75: heat shock protein family A (Hsp70) member 9; ITPR/IP3R: inositol 1,4,5-trisphosphate receptor; MAM: mitochondria-associated endoplasmic reticulum membrane; MCU: mitochondrial calcium uniporter; MFN2: mitofusin 2; OCR: oxygen consumption rate; ROS: reactive oxygen species; ROT/AA: rotenone+antimycin A; VDAC1: voltage dependent anion channel 1; WLS: Wolfram-like syndrome; WS: Wolfram syndrome; WT: wild-type.

Wfs1E864K knock-in mice illuminate the fundamental role of Wfs1 in endocochlear potential production.

Wolfram syndrome (WS) is a rare neurodegenerative disorder encompassing diabetes mellitus, diabetes insipidus, optic atrophy, hearing loss (HL) as well as neurological disorders. None of the animal models of the pathology are presenting with an early onset HL, impeding the understanding of the role of Wolframin (WFS1), the protein responsible for WS, in the auditory pathway. We generated a knock-in mouse, the Wfs1E864K line, presenting a human mutation leading to severe deafness in affected individuals. The homozygous mice showed a profound post-natal HL and vestibular syndrome, a collapse of the endocochlear potential (EP) and a devastating alteration of the stria vascularis and neurosensory epithelium. The mutant protein prevented the localization to the cell surface of the Na+/K+ATPase ß1 subunit, a key protein for the maintenance of the EP. Overall, our data support a key role of WFS1 in the maintenance of the EP and the stria vascularis, via its binding partner, the Na+/K+ATPase ß1 subunit.

Improvements in Clinician, Organization, and Patient Outcomes Make a Compelling Case for Evidence-Based Practice Mentor Development Programs: An Integrative Review.

BACKGROUND: Many organizations struggle to systematically integrate EBP into practice. EBP mentors address organizational barriers and promote the translation of evidence into clinical practice at the bedside. AIM: To evaluate research findings related to EBP mentor development programs, to identify effective practices, and to assess the outcomes associated with EBP mentor development programs. METHODS: A comprehensive review of the literature was conducted to retrieve studies from CINAHL, PubMed, and Scopus, using keywords and subject headers related to EBP mentorship and quality and safety outcomes. Studies were appraised and reviewed to compare mentor program composition and examine clinician, organizational, and patient outcomes. RESULTS: Fifteen studies met inclusion criteria: one randomized control trial (RCT), one literature review, eleven descriptive studies, and two case reviews. Most programs included didactic content, an EBP project with coaching, and resources to support learning. The studies found that these programs led to improvements in clinicians' EBP beliefs, practices, and abilities, the organization's readiness for EBP, and patient safety. LINKING EVIDENCE TO ACTION: There is solid justification for healthcare organizations to invest in an EBP mentor development program.