Genetic linkage analysis and DNA[10] sequencing have shown that CADASIL is caused by mutations in the human Notch3 gene at locus chromosome 19p13.[11]

Notch3 belongs to the family of highly conserved Notch/LIN-12 receptors, which includes four members in vertebrates.[12] This gene has 33 exons and encodes for a TM receptor that is a component of an intercellular signaling pathway essential for controlling cell fate during development in a wide range of organisms, including insects, nematodes, and mammals.[13] The Notch3 molecule is synthesized as a 2321-amino acid precursor containing all typical Notch motifs, namely, an extracellular region exhibiting a signal sequence and an extracellular domain (NECD) with 34-tandem epidermal growth factor (EGF)-like repeats followed by three Notch/ LIN-12 repeats, a TM segment, and an intracellular domain (NICD) containing six cdc10/ankyrin repeats flanked by two nuclear localization signals (Fig. 3).[12,13] During maturation and activation, Notch3 undergoes three proteolytic cleavages (Fig. 3). The first cleavage (S1) occurs in the Golgi apparatus where a furine-like convertase cleaves Notch between its NCID and its NECD. After the reappearance of these two domains, they bind to each other to generate a heterodimeric receptor. At

Fig. 3 (A) Preferential location of mutations on Notch3 EGF repeats involved in CADASIL Notch3 protein. (B) Schematic representation of the three cleavages (S1, S2, and S3) that occur during Notch3 maturation.

the cell surface, the receptor interacts with ligands, Jagged-1 or Delta-1, which are TM proteins expressed to juxtaposed cells.[12] Ligand interaction leads to a second cleavage (S2) of the receptor. A metalloprotease ADAM-17, also called TNFa-converting enzyme (TACE), cleaves the NECD, precisely 12 amino acids outside of the plasma membrane. This cleavage releases the NECD to the extracellular space. The third cleavage is the result of the g-secretase complex formed by nicastrine, preseniline1, and preseniline2. This last cleavage releases the NCID, which translocates to the nucleus, where it regulates transcription associated with a DNA-binding protein CSL (RBP-Jk) (Fig. 3).[12]

Molecular screening of all 33 coding exons within a large panel of CADASIL patients revealed that most of the mutations are missense mutations;[11] other mutations including splice site mutations and deletions, which have been identified in a few patients, lead to small in-frame deletions.[14] All the mutations are located within the EGF-like repeats of the NECD, with a strong clustering within exons 3 and 4, which encode the first five EGF repeats (Fig. 3).[15] CADASIL mutations are highly stereotyped, leading to an odd number of cysteine residues within an EGF-like repeat.[15]

Getting Started With Dumbbells

Getting Started With Dumbbells

The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.

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