Module 9 Short Summary

When considering the genetics of human disease it is important to keep in mind that similar symptoms or disease can result from mutations in different genes. A good example of this is Alzheimers disease. While many cases of Alzheimers disease arise sporadically, there are familial forms of the disease that can result from mutations in any of a number of genes.

Alzheimers disease develops, at least in part, from the accumulation, around neurons, of plaques that are composed of the b-amyloid peptide. The b-amyloid peptide is a proteolytic fragment generated from the b-amyloid precursor protein (bAPP). bAPP is a membrane spanning protein that can be processed in two ways by a series of enzymes termed secretases (alpha, beta, and gamma). If bAPP is clipped first by alpha-secretase and then by gamma-secretase, harmless protein fragments are generated. However, if bAPP is first processed by beta-secretase, the b-amyloid peptide can be produced.

As might be expected, genetic studies have demonstrated that mutations in the gene encoding bAPP that result in its abnormal processing cause Alzheimers disease. In addition, it was also found that mutations in another set of genes called the presenilins are the cause of other forms of familial Alzheimers disease. Disease causing mutations in the presenilins, which can be dominant, enhance the processing of bAPP into b-amyloid peptide. The presenilins are membrane bound proteins that are involved in the proteolytic processing of other proteins (and are candidates for being the as yet uncharacterized gamma secretase). Hence, mutations in several different genes all have the same outcome; increased production of b-amyloid peptide and the development of Alzheimers disease.