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        Normal Proteolytic Processing of the Presenilins

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        The majority of familial Alzheimer’s disease (AD) cases are linked to mutations of the presenilin 1 and 2 (PS1, PS2 ) genes on chromosomes 14 and 1, respectively (1 -3 ). PS1 and PS2 are about 67% identical in amino acid sequence. Based on hydrophobicity analysis, the presenilins are predicted to have multiple transmembrane domains. Structural analysis (see Chapter 19 }) suggest that presenilins are 6-8 transmembrane proteins which are located in the endoplasmic reticulum (ER) and Golgi. The N- and C-termini and the large hydrophilic loop region are oriented to the cytoplasm (4 ,5 ). More than 40 AD-causing mutations have been identified in PS1 , whereas only two mutations have been identified in PS2. The disease-causing mutations span most domains of the protein, with clusters of mutations in the second transmembrane domain and the large hydrophilic loop region Fig. 1 ).
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