gamma-secretases: from cell biology to therapeutic strategies.
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.
Department of Molecular and Developmental Genetics, VIB, Leuven, Belgium; Center for Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium.
Bruno A
BA
Bergmans
Bart
B
De Strooper
D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D053829:Amyloid Precursor Protein Secretases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D003585:Cell Biology; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D009154:Mutation / Q000235:genetics; D009422:Nervous System Diseases / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D053763:Presenilins / Q000235:genetics
D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D053763:Presenilins; D053829:Amyloid Precursor Protein Secretases