Neurodegeneration in Alzheimer’s disease (AD) is closely associated with accumulation of pathologic tau aggregates in the form of neurofibrillary tangles. We found that a p.Asp395Gly mutation in VCP 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. Additionafsupplly, intracerebral microinjection of pathologic tau led to increased tau aggregates in p.Asp395Gly VCP knock-in mice compared to injected wild-type mice. These findings suggest that p.Asp395Gly VCP is an autosomal dominant genetic mutation associated with neurofibrillary degeneration in part due to reduced tau disaggregation, raising the possibility that VCP may represent a therapeutic target for the treatment of AD.

BACKGROUNDDementia negatively impacts quality of life and is likely to become more prevalent in the rapidly aging population of the United States. It is estimated that the number of people living with dementia will triple by 2050 and care of these patients will cost approximately $1.5 trillion annually. In addition, dementia places an enormous emotional toll on a patient's family and loved ones. Targeting modifiable risk factors may delay further cognitive decline and help manage dementia, providing therapeutic, financial, and social benefit to the patient, their family, and the healthcare system.

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 aggregates. 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.

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.

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