Role of the proteasome in Alzheimer's disease.
The proteasome is a multicatalytic complex involved in the degradation of polyubiquitinated proteins. Here we review the clues of a possible involvement of the proteasome in Alzheimer's disease neuropathology. Thus, we discuss the fact that the proteasome modulates the intracellular concentrations of presenilins 1 and 2. These two proteins, when mutated, appear responsible for most of early onset forms of Alzheimer's disease and this is thought to be due to the exacerbation of the pathogenic pathway of the maturation of the beta-amyloid precursor protein. Controlling presenilins concentrations could have drastic repercussions on cell physiology as suggested by the fact that proteasome inhibitors drastically potentiate the 'normal' or 'pathogenic' presenilins phenotype related with betaAPP processing. The possibility of considering the proteasome as a potential target for therapeutic intervention in Alzheimer's disease is discussed.
Checler
F
F
Institut de Pharmacologie Moléculaire et Cellulaire, UPR411 du CNRS, Sophia Antipolis, Valbonne, France. checler@ipmc.cnrs.fr
da Costa
C A
CA
Ancolio
K
K
Chevallier
N
N
Lopez-Perez
E
E
Marambaud
P
P
D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D015195:Drug Design; D010450:Endopeptidases / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D018390:Gene Targeting; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D058225:Plaque, Amyloid / Q000378:metabolism; D053764:Presenilin-1; D053766:Presenilin-2; D046988:Proteasome Endopeptidase Complex; D014452:Ubiquitins / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; D009097:Multienzyme Complexes; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D014452:Ubiquitins; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D046988:Proteasome Endopeptidase Complex