VCP activator reverses nuclear proteostasis defects and enhances TDP-43 aggregate clearance in multisystem proteinopathy models.

Pathogenic variants in valosin-containing protein (VCP) cause multisystem proteinopathy (MSP), a disease characterized by multiple clinical phenotypes including inclusion body myopathy, Paget's disease of the bone, and frontotemporal dementia (FTD). How such diverse phenotypes are driven by pathogenic VCP variants is not known. We found that these diseases exhibit a common pathologic feature: ubiquitinated intranuclear inclusions affecting myocytes, osteoclasts, and neurons. Moreover, knock-in cell lines harboring MSP variants show a reduction in nuclear VCP. Given that MSP is associated with neuronal intranuclear inclusions comprised of TDP-43 protein, we developed a cellular model whereby proteostatic stress results in the formation of insoluble intranuclear TDP-43 aggregates. Consistent with a loss of nuclear VCP function, cells harboring MSP variants or cells treated with VCP inhibitor exhibited decreased clearance of insoluble intranuclear TDP-43 aggregates. Moreover, we identified 4 compounds that activate VCP primarily by increasing D2 ATPase activity, where pharmacologic VCP activation appears to enhance clearance of insoluble intranuclear TDP-43 aggregate. Our findings suggest that VCP function is important for nuclear protein homeostasis, that impaired nuclear proteostasis may contribute to MSP, and that VCP activation may be a potential therapeutic by virtue of enhancing the clearance of intranuclear protein aggregates.

Novel VCP activator reverses multisystem proteinopathy nuclear proteostasis defects and enhances TDP-43 aggregate clearance.

Pathogenic variants in VCP cause multisystem proteinopathy (MSP), a disease characterized by multiple clinical phenotypes including inclusion body myopathy, Paget's disease of the bone, and frontotemporal dementia (FTD). How such diverse phenotypes are driven by pathogenic VCP variants is not known. We found that these diseases exhibit a common pathologic feature, ubiquitinated intranuclear inclusions affecting myocytes, osteoclasts and neurons. Moreover, knock-in cell lines harboring MSP variants show a reduction in nuclear VCP. Given that MSP is associated with neuronal intranuclear inclusions comprised of TDP-43 protein, we developed a cellular model whereby proteostatic stress results in the formation of insoluble intranuclear TDP-43 aggregates. Consistent with a loss of nuclear VCP function, cells harboring MSP variants or cells treated with VCP inhibitor exhibited decreased clearance of insoluble intranuclear TDP-43 aggregates. Moreover, we identified four novel compounds that activate VCP primarily by increasing D2 ATPase activity whereby pharmacologic VCP activation appears to enhance clearance of insoluble intranuclear TDP-43 aggregate. Our findings suggest that VCP function is important for nuclear protein homeostasis, that MSP may be the result of impaired nuclear proteostasis, and that VCP activation may be potential therapeutic by virtue of enhancing the clearance of intranuclear protein aggregates.

Rates of Sensorineural Hearing Loss and Revision Surgery After Stapedotomy: A Single-institution Experience Using the Nitinol Prosthesis.

Background: Historically, stapedectomy complication rates are quoted as 1% profound postoperative sensorineural hearing loss (SNHL), 5%-10% nonprofound SNHL, and 5%-10% revision surgery. Objective: We sought to reassess rates of post-stapedotomy complications based on our experience using contemporary surgical technique. Methods: A retrospective case series was carried out at an academic tertiary referral center. Adult patients undergoing stapedotomy from 2013 to 2020 were included. Primary outcomes were rates of hearing loss and revision surgery. Rates of dizziness, tinnitus, dysgeusia, and proportions of patients who achieved air-bone gap (ABG) closure at 8-12 weeks postoperatively were also assessed. Results: Four hundred sixty-eight stapedotomies in 399 patients with a median follow-up duration of 99 days (range, 11-5134) were reviewed. One patient (0.21%) suffered profound SHNL and 15 (3.20%) patients suffered nonprofound SNHL. The revision rate for stapedotomies from our institution was 4.49% (21 total revision surgeries). In 277 operations (59.19%), the patient had closure of the ABG within 10 dB. A further 132 (28.21%) had closure of the ABG between 10 and 20 dB. Air pure-tone audiometry scores improved by an average of 25.03 dB. Eighty-three (17.74%) patients complained of postoperative dizziness, which resolved by the time of the first follow-up appointment in all but 26 (5.56%). Seventeen patients (3.63%) complained of tinnitus, and 22 (4.70%) complained of dysgeusia. Conclusions: SNHL, complications, and revision rates for stapedotomy in the modern era may be substantially lower than those currently presented to patients based on classic techniques and historical data.

Fibroid expulsion: a unique presentation of mechanical small bowel obstruction 11 years after uterine artery embolization: a case report.

BACKGROUND: Uterine artery embolization in the treatment of uterine leiomyoma has been rarely associated with dislodgement and expulsion of infarcted uterine fibroids through the vagina, peritoneum, or bowel wall, predominantly occurring within 6 months of uterine artery embolization. CASE PRESENTATION: We present the case of a 54-year-old African American woman who underwent uterine artery embolization 11 years prior and developed mechanical small bowel obstruction from the migration of fibroid through a uteroenteric fistula with ultimate impaction within the distal small bowel lumen. Small bowel resection and hysterectomy were curative. CONCLUSIONS: Uteroenteric fistula with small bowel obstruction due to fibroid expulsion may present as a delayed finding after uterine artery embolization and requires heightened awareness.

Autosomal dominant VCP hypomorph mutation impairs disaggregation of PHF-tau.

Neurodegeneration in Alzheimer's disease (AD) is closely associated with the accumulation of pathologic tau aggregates in the form of neurofibrillary tangles. We found that a p.Asp395Gly mutation in VCP (valosin-containing protein) was associated with dementia characterized neuropathologically by neuronal vacuoles and neurofibrillary tangles. Moreover, VCP appeared to exhibit tau disaggregase activity in vitro, which was impaired by the p.Asp395Gly mutation. Additionally, intracerebral microinjection of pathologic tau led to increased tau aggregates in mice in which p.Asp395Gly VCP mice was knocked in, as compared with injected wild-type mice. These findings suggest that p.Asp395Gly VCP is an autosomal-dominant genetic mutation associated with neurofibrillary degeneration in part owing to reduced tau disaggregation, raising the possibility that VCP may represent a therapeutic target for the treatment of AD.