Reticular hyperpigmentation
Dimitris Rigopoulos, Alexander C. Katoulis in Hyperpigmentation, 2017
RAK is a rare genodermatosis that is inherited in an autosomal dominant manner, and is caused by mutations on the ADAM10 gene, mapped on chromosome 15q21.3.77 The exact incidence of the condition is unknown. In general, cases have been reported in association with most ethnic backgrounds; however, the vast majority of patients are of Japanese origin.77 A number of authors have suggested that RAK should be considered a variant of DDD; however, this remains highly controversial, as the two disorders are caused by different gene mutations and exhibit distinct phenotypes. In RAK, loss-of-function mutations in ADAM10 are commonly observed.77 The ADAMs are considered a new gene family that belong to the zinc protease superfamily.78,79 More specifically, ADAM10 has been shown to play a role in the ectodomain shedding of various substrates in the skin, such as the L1 cell adhesion molecule (L1-CAM), CD44, E-cadherin, N-cadherin, IL-6R, and CD30.80 At this point, the exact pathogenetic mechanism of RAK is not well understood, but ADAM10 haploinsufficiency was recently reported to cause freckle-like macules in specific murine models.81
Pharmacology of Withanolide A
Amritpal Singh Saroya in Contemporary Phytomedicines, 2017
Withanolide A and asiatic acid were investigated for their potential activities against multiple targets associated with Abeta pathways (BACE1, ADAM10, IDE, and NEP). BACE1 is a rate-limiting enzyme in the production of Abeta from amyloidbeta precursor protein (AbetaPP), while ADAM10 is involved in non-amyloidogenic processing of AbetaPP. IDE and NEP are two of the prominent enzymes involved in effectively degrading Abeta.
Ageing, Neurodegeneration and Alzheimer's Disease
James N. Cobley, Gareth W. Davison in Oxidative Eustress in Exercise Physiology, 2022
The identification of a small peptide named Aβ as the major constituent of the extracellular plaques was a driving factor in the development of the ‘Amyloid-Cascade Hypothesis’, which placed Aβ at the centre of AD research (Hardy and Higgins, 1992). This was supported by evidence of neighbouring neuritic and glial cytopathology in regions associated with memory and cognition near Aβ deposits (Selkoe and Hardy, 2016). Further, mutations within and close to the Aβ region in the APP gene are associated with aggressive autosomal dominant forms of familial AD (fAD) (Hunter and Brayne, 2018). The most common cause of fAD is missense mutations to the PSEN1 and PSEN2 genes, which are known to impact the catalytic subunit of the γ-secretase enzyme (Kelleher and Shen, 2017). γ-Secretase is responsible for a critical step in Aβ generation following beta amyloid cleaving enzyme-1 (BACE-1) cleavage of the amyloid-β precursor protein (AβPP). In many cases, PSEN1/2 mutations increase Aβ production or increase the ratio of the longer Aβ1–42 to the more physiological Aβ1–40 peptide (Sun et al., 2017). Aβ1–42 can more rapidly aggregate at lipid membranes and form oligomeric Aβ species. These oligomers accumulate in endocytotic vesicles, and thus, an increase in the Aβ1–42:Aβ1–40 ratio has been linked to AD development (Zheng et al., 2017). Aβ1–42 has been shown to more easily propagate from smaller tetra- and hexameric oligomers to larger aggregates when compared to more resistant Aβ1–40 tetramers (Bernstein et al., 2009). The appearance of such ‘intermediate’ oligomeric forms of Aβ that are particularly toxic to neurons has provided a new area of investigation for the role of Aβ in the pathology of AD (Kim et al., 2003; Lesné et al., 2008). Further, Aβ oligomers have also been shown to diffuse from Aβ fibrillar plaques (Koffie et al., 2009) and exert cytotoxic effects which are associated with synapse loss and cognitive decline (Pickett et al., 2016). The processing of AβPP is not limited to BACE-1 cleavage and can be initiated by the enzyme ‘a disintegrin and metalloproteinase-10’ (ADAM10) (Kuhn et al., 2010) (Figure 16.1). ADAM10 cleavage of AβPP cuts through the Aβ-region and leads to shedding of soluble AβPPα. The sequential cleavage by γ-secretase releases a truncated p3 peptide, thus preventing the generation of Aβ (Kuhn et al., 2010). In AD, the expression and activity of ADAM10 are lower, which may increase the proteolytic processing of AβPP by BACE-1 and thus increase Aβ generation. Further, the soluble fragment AβPPα plays a role in neurogenesis, maintaining synaptic function and supporting the formation of neuronal networks (Kögel et al., 2012; Yuan et al., 2017), and is considered neuroprotective. Missense mutations to the ADAM10 gene affecting the cysteine switch in the prodomain of the translated enzyme are also associated with an increased risk of AD (Kim et al., 2009). All of this evidence provides significant data for a role of Aβ in the progression of AD.
Trophectoderm non-coding RNAs reflect the higher metabolic and more invasive properties of young maternal age blastocysts
Published in Systems Biology in Reproductive Medicine, 2023
Panagiotis Ntostis, Grace Swanson, Georgia Kokkali, David Iles, John Huntriss, Agni Pantou, Maria Tzetis, Konstantinos Pantos, Helen M. Picton, Stephen A. Krawetz, David Miller
TSPAN15 is an essential subunit of the ADAM10 scissor complex, which is also important for early embryo development (Koo et al. 2020). The lncRNA TSPAN15 (NR_147091) was expressed approximately 6.5 times more in the YMA/rba-YMA than in the AMA/rba-AMA blastocysts. ADAM10 is involved in cell junctions and blastocyst formation and is essential for preimplantation embryo development (Kwon et al. 2016). A knockout mouse model illustrated that ADAM10 is also involved in embryonic cardiovascular development causing embryonic death after day 10.5 (Zhang C et al. 2010). Perhaps the role TSPAN15 plays in the formation of cell junctions and its higher expression in blastocysts with an increased capacity to implant into the endometrium is indicative of a greater likelihood of successful mammalian early embryo development (Eckert and Fleming 2008; Estill et al. 2019).
The cellular prion protein and its derived fragments in human prion diseases and their role as potential biomarkers
Published in Expert Review of Molecular Diagnostics, 2019
Katrin Thüne, Matthias Schmitz, Anna Villar-Piqué, Hermann Clemens Altmeppen, Markus Schlomm, Saima Zafar, Markus Glatzel, Franc Llorens, Inga Zerr
During prion disease, the metalloproteinase ADAM10 is able to shed both, PrPC and PrPSc, from the cell membrane resulting in the release of almost full-length anchorless forms of both kinds into the extracellular environment [30,70,71]. While physiologically shed PrP is thought to be protective, shedding of PrPSc by ADAM10 could generate new sources of infectivity and enhance prion spread within the brain and beyond, indicating a dual role of the protease in these diseases [41,42,69]. ADAM10 cleaves human PrP at the C-terminus, yet the exact proteolytic cleavage site is not unambiguously defined. Based on data obtained for other (transmembrane) substrates of ADAM10, it is possible that the protease generates different variants of shed PrP [8,72]. The PK-resistant fragment PrP226* has been proposed as one variant that might propagate disease in higher concentrations (Figure 2) [8,25]. Further studies are required to gain better insight in that regard. Interestingly, the metalloprotease ADAM10 has been shown to cleave, beside PrP, further numerous protein substrates within the plasma membrane. In this context, ADAM10 was reported to be involved in Aβ metabolism and is considered as a risk gene in Alzheimer’s disease [124].
Specific ADAM10 inhibitors localize in exosome-like vesicles released by Hodgkin lymphoma and stromal cells and prevent sheddase activity carried to bystander cells
Published in OncoImmunology, 2018
Francesca Tosetti, Roberta Venè, Caterina Camodeca, Elisa Nuti, Armando Rossello, Cristina D'Arrigo, Denise Galante, Nicoletta Ferrari, Alessandro Poggi, Maria Raffaella Zocchi
An ADAM10 soluble form (sADAM10) is apparently present in the CM of RS773 cells as a band of MW intermediate between mature ADAM10 and the precursor form (Figure 1C). The evidence that ADAM10, besides initiating intramembrane proteolysis of several substrates, is itself subject to a proteolytic cascade is growing. MSC ExoV were also analyzed upon TEM visualization, as shown in Figure 1D (average dimension: 60% 50–100 nm, 40% 100–200 nm). ADAM10 silencing in MSC773 cells determined a decrease both in cytoplasmic and in ExoV content, confirming the role of stromal ExoV as ADAM10 extracellular carriers. On the other hand, the exosomal markers CD81 and CD63 are unaffected by ADAM10 silencing (Figure 1E). Moreover, ADAM10 silencing in MSC773 resulted in reduced ADAM10 surface expression (Suppl. Fig. 2A) and sMICA shedding (Suppl. Fig. 2B).
Related Knowledge Centers
- Alpha Secretase
- Cell Adhesion
- Ephrin Receptor
- Protease
- Protein
- Protein Domain
- Gene
- Adam
- Sheddase
- Neuron