Department of Molecular and Developmental Genetics, VIB, Leuven, Belgium; Center for Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium.
Lancet Neurol. 2010 Feb;9(2):215-26. doi: 10.1016/S1474-4422(09)70332-1.
Presenilins form the catalytic part of the gamma-secretases, protein complexes that are responsible for the intramembranous cleavage of transmembrane proteins. The presenilins are involved in several biological functions, but are best known for their role in the generation of the beta-amyloid (Abeta) peptide in Alzheimer's disease and are therefore thought to be important drug targets for this disorder. Mutations in the presenilin genes cause early-onset familial Alzheimer's disease, but mutation carriers have substantial phenotypic heterogeneity. Recent evidence implicating presenilin mutations in non-Alzheimer's dementias, including frontotemporal dementia and Lewy body dementia, warrants further investigation. An increased understanding of the diversity of the molecular cell biology of the gamma-secretase complex and the effects of clinical mutations in the presenilin genes might help pave the way for improved development of drugs that are designed to target gamma-secretase enzymatic activity in Alzheimer's disease and potentially in other neurological diseases.
早老素蛋白构成γ-分泌酶的催化部分，γ-分泌酶是负责跨膜蛋白的膜内裂解的蛋白复合物。早老素蛋白参与多种生物学功能，但最著名的是其在阿尔茨海默病中β-淀粉样肽（Abeta）生成中的作用，因此被认为是这种疾病的重要药物靶点。早老素基因突变导致早发性家族性阿尔茨海默病，但突变携带者具有显著的表型异质性。最近有证据表明，早老素基因突变与非阿尔茨海默病痴呆症有关，包括额颞叶痴呆和路易体痴呆，这需要进一步研究。对γ-分泌酶复合物的分子细胞生物学多样性以及早老素基因突变的临床影响的进一步了解，可能有助于为旨在靶向阿尔茨海默病和可能的其他神经退行性疾病中γ-分泌酶酶活性的药物的开发铺平道路。
