SHARPIN: Role in Finding NEMO and in Amyloid-Beta Clearance and Degradation (ABCD) Pathway in Alzheimer's Disease?

SHANK- associated RH domain-interacting protein (SHARPIN) is a multifunctional protein associated with numerous physiological functions and many diseases. The primary role of the protein as a LUBAC-dependent component in regulating the activation of the transcription factor NF-κB accounts to its role in inflammation and antiapoptosis. Hence, an alteration of SHARPIN expression or genetic mutations or polymorphisms leads to the alteration of the above-mentioned primary physiological functions contributing to inflammation-associated diseases and cancer, respectively. However, there are complications of targeting SHARPIN as a therapeutic approach, which arises from the wide-range of LUBAC-independent functions and yet unknown roles of SHARPIN including neuronal functions. The identification of SHARPIN as a postsynaptic protein and the emerging studies indicating its role in several neurodegenerative diseases including Alzheimer's disease suggests a strong role of SHARPIN in neuronal functioning. This review summarizes the functional roles of SHARPIN in normal physiology and disease pathogenesis and strongly suggests a need for concentrating more studies on identifying the unknown neuronal functions of SHARPIN and hence its role in neurodegenerative diseases.

Women with drug-resistant epilepsy: Surgery or pregnancy first?

OBJECTIVE: We compared women with drug-resistant focal epilepsy who had undergone surgery (WWE-S) with those who were managed medically (WWE-M) for maternal and fetal outcomes of their pregnancies. METHODS: We classified all WWE-S who were enrolled in a prospective registry of epilepsy and pregnancy (1998-2015) as those who underwent the surgery before pregnancy (WWE-SF) or after pregnancy (WWE-PF). The comparator group (WWE-M) was twice that number of age-matched women with focal epilepsy in this registry. Their clinical profile, anti-epileptic drug (AED) use, and pregnancy outcomes were extracted from the records of the registry. RESULTS: The number of completed pregnancies with known outcome was 74 for WWE-S (67 WWE-SF and 7 WWE-PF) and 134 for WWE-M. Seizures increased during pregnancy for fewer WWE-SF than for WWE-M (14.9% vs 39.6%, P = .001). Compared to WWE-M, fewer WWE-SF had dose escalation during pregnancy (28.4% vs 14.9%, P = .025). Preterm deliveries were more frequent in WWE-SF than WWE-M (24.6% vs 12.2%, P = .029). The differences between the WWE-SF and WWE-M regarding the rates of fetal loss (10.4% vs 6.7%, P = .255), major congenital malformations (8.5% vs. 11.1%, P = .395), and development quotient at 1 year of age <85 (42.5% vs 42.3%, P = .569) were not statistically significant. Compared to WWE-PF, fewer WWE-SF had AED dose escalation (14.9% vs 85.7%, P = .001) or increase in seizures (14.9% vs 100%, P = .001) during pregnancy. WWE-SF had fewer infants with development quotient <85 (41.0% vs 100%, P = .005). SIGNIFICANCE: WWE-SF can expect better control of seizures and decreased AED burden during pregnancy than WWE with focal epilepsies managed with medicines only. WWE who undergo surgery for epilepsy before their pregnancies can expect fewer seizures and lower AED burden during pregnancy.

Apolipoprotein E Polymorphism and Oxidative Stress in Peripheral Blood-Derived Macrophage-Mediated Amyloid-Beta Phagocytosis in Alzheimer's Disease Patients.

Peripheral blood-derived macrophages isolated from Alzheimer's disease (AD) patients have earlier been reported to demonstrate ineffective phagocytosis of amyloid-beta compared to the age-matched control subjects. However, the mechanisms causing unsuccessful phagocytosis remain unclear. Oxidative stress and the presence of ApoEε4 allele has been reported to play a major role in the pathogenesis of AD, but the contribution of oxidative stress and ApoEε4 in macrophage dysfunction leading to ineffective Aß phagocytosis needs to be analyzed. Aß phagocytosis assay has been performed using FITC-labeled Aß and analyzed using flow cytometry and confocal imaging in patient samples and in THP-1 cells. Oxidative stress in patient-derived macrophages was analyzed by assessing the DNA damage using comet assay. ApoE polymorphism was analyzed using sequence-specific PCR and Hixson & Vernier Restriction isotyping protocol. In this study, we have analyzed the patterns of phagocytic inefficiency of macrophages in Indian population with a gradual decline in the phagocytic potential from mild cognitive impairment (MCI) to AD patients. Further, we have shown that the presence of ApoEε4 allele might also have a possible effect on the phagocytosis efficiency of the macrophages. Here, we demonstrate for the first time that oxidative stress could affect the amyloid-beta phagocytic potential of macrophages and hence by alleviating oxidative stress using curcumin, an anti-oxidant could enhance the amyloid-beta phagocytic efficacy of macrophages of patients with AD and MCI, although the responsiveness to curcumin might depends on the presence or absence of APOEε4 allele. Oxidative stress contributes significantly to decreased phagocytosis of Aß by macrophages. Moreover, the phagocytic inefficiency of macrophages was correlated to the presence of ApoEε4 allele. This study also found that the Aß-phagocytic potential of macrophage gets significantly enhanced in curcumin-treated patient-derived macrophages.

A novel role for SHARPIN in amyloid-ß phagocytosis and inflammation by peripheral blood-derived macrophages in Alzheimer's disease.

Defective immune cell-mediated clearance of amyloid-beta (Aß) and Aß-associated inflammatory activation of immune cells are key contributors in pathogenesis of Alzheimer's disease (AD). However, the underlying mechanisms remain elusive. Shank-associated RH domain-interacting protein (SHARPIN) is a critical regulator of inflammatory response. Using in vitro cultures of THP-1-derived macrophages exposed to Aß and AD patient-derived macrophages, we demonstrate the role of SHARPIN as an obligate regulator of Aß phagocytosis and inflammation in macrophages. Specifically, Aß-stimulated SHARPIN in THP-1 macrophages promoted Aß phagocytosis and expression of proinflammatory markers. In addition, Aß-stimulated SHARPIN in macrophages promoted neuronal cell-death in differentiated SHSY5Y neurons. Furthermore, we report a novel regulatory link between SHARPIN and the NLRP3 inflammasome in response to Aß in THP-1 macrophages. In line with our in vitro observations, a strong positive association was demonstrated between levels of Aß42 in blood plasma of mild cognitive impairment and AD patients with SHARPIN expression in macrophages obtained from respective patient-derived peripheral blood mononuclear cells. Together, our findings show SHARPIN as a critical determinant in mediating macrophage response to Aß and pathogenesis of AD.