Partial loss of presenilins causes seborrheic keratosis and autoimmune disease in mice.
نویسندگان
چکیده
Presenilin (PS1) and (PS2) are the centers of gamma-secretase that release Abeta from APP in Alzheimer's disease (AD). They cleave signaling proteins like Notch and downregulate beta-catenin to modulate Wnt signaling. Inactivation of PS1 or PS1 and PS2 causes a prenatally lethal 'Notch phenotype,' which has hampered investigation of PS function in adulthood seriously. We have thus turned towards PS1+/-PS2-/- mice which carry the most severe reduction of PS alleles compatible with survival, to analyze the consequences of impaired PS function especially in adulthood. In these 'partial deficient' mice, PS1 protein concentration is considerably lowered, functionally reflected by reduced gamma-secretase activity and impaired beta-catenin downregulation. Their phenotype is normal up to approximately 6 months, when the majority of the mice develop an autoimmune disease characterized by dermatitis, glomerulonephritis, keratitis and vasculitis, as seen in human systemic lupus erythematosus. Besides B-cell dominated infiltrates, we observe a hypergammaglobulinemia with immune complex deposits in several tissues, high-titer nuclear autoantibodies and an increased CD4+/CD8+ ratio. The mice further develop a benign skin hyperplasia similar to human seborrheic keratosis as opposed to malignant keratocarcinomata observed in skin-specific PS1 'full' knockouts. A partial reduction of PS function in PS1+/-PS2-/- mice causes a novel phenotype in adulthood unrelated to the developmental defects of full knockouts. As PS1+/-PS2+/- mice remain healthy, this points towards a sharply defined minimum of PS function. Skin and immune system appear to be especially sensitive targets of impaired PS function and may need careful monitoring if gamma-secretase inhibitors are envisaged for treating AD.
منابع مشابه
Eficacy of calcipotriol in the treatment of seborrheic keratosis: a pilot study
Background: Seborrheic keratosis is a common benign tumor and many modalities are used to treat it. No convincing data favors the therapeutic effect of calcipotriol on seborrheic keratosis. We aimed to assess the efficacy of calcipotriol in the treatment of this tumor.Method: Eligible patients aged over 40 years with seborrheic keratosis (size: 5-15mm) were instructed to apply 50?g/g calcipotri...
متن کاملAssociation of pulmonary leiomyoma with seborrheic keratosis
A 58 year old man was referred to suegery clinic due to dyspnea and left sided chest wall pain for three months duration.during the last 18 months some monomorph disseminated hyperkeratotic skin lesions appeared on his face and trunk.after worlup and evaluation of the patient,he underwent thoracotomy with indication of presence of a mass in the left lung.the operative finding was a huge solid r...
متن کامل[Squamous cell carcinoma on seborrheic keratosis].
To the Editor: Seborrheic keratosis is one of the most common benign epidermal tumors in dermatologic clinical practice. Although the association between seborrheic keratosis and other skin tumors was first reported in 1932, its malignant transformation is very rare, with less than 20 published cases. We present the case of a patient with seborrheic keratosis that underwent transformation into ...
متن کاملBowenoid transformation in seborrheic keratosis: A retrospective analysis of 429 patients
BACKGROUND Seborrheic keratosis is a common, benign skin tumor. Numerous reports have shown its possibility of malignant transformation. This study was designed to demonstrate the occurrence of concomitant seborrheic keratosis and skin cancers. MATERIALS AND METHODS Data was retrospectively reviewed from all patients with a diagnosis of seborrheic keratosis in pathology department of Alzahra ...
متن کاملGiant Hidroacanthoma Simplex Mimicking Bowen's Disease
Hidroacanthoma simplex is a benign tumor of the skin, macroscopically resembling seborrheic keratosis or Bowen's disease and histologically mimicking clonal-type seborrheic keratosis. We observed a plaque of 70 × 50 mm on the right flank part. From clinical appearance, we suspected Bowen's disease; however, based on immunohistochemical findings, we made a diagnosis of hidroacanthoma simplex.
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- Human molecular genetics
دوره 13 13 شماره
صفحات -
تاریخ انتشار 2004