Expression of Alzheimer's disease-associated presenilin-1 is controlled by proteolytic degradation and complex formation.
Numerous mutations causing early onset Alzheimer's disease have been identified in the presenilin (PS) genes, particularly the PS1 gene. Like the mutations identified within the beta-amyloid precursor protein gene, PS mutations cause the increased generation of a highly neurotoxic variant of amyloid beta-peptide. PS proteins are proteolytically processed to an N-terminal approximately 30-kDa (NTF) and a C-terminal approximately 20-kDa fragment (CTF20) that form a heterodimeric complex. We demonstrate that this complex is resistant to proteolytic degradation, whereas the full-length precursor is rapidly degraded. Degradation of the PS1 holoprotein is sensitive to inhibitors of the proteasome. Formation of a heterodimeric complex is required for the stability of both PS1 fragments, since fragments that do not co-immunoprecipitate with the PS complex are rapidly degraded by the proteasome. Mutant PS fragments not incorporated into the heterodimeric complex lose their pathological activity in abnormal amyloid beta-peptide generation even after inhibition of their proteolytic degradation. The PS1 heterodimeric complex can be attacked by proteinases of the caspase superfamily that generate an approximately 10-kDa proteolytic fragment (CTF10) from CTF20. CTF10 is rapidly degraded most likely by a calpain-like cysteine proteinase. From these data we conclude that PS1 metabolism is highly controlled by multiple proteolytic activities indicating that subtle changes in fragment generation/degradation might be important for Alzheimer's disease-associated pathology.
Steiner
H
H
Central Institute of Mental Health, Department of Molecular Biology, J5, 68159 Mannheim, Germany.
Capell
A
A
Pesold
B
B
Citron
M
M
Kloetzel
P M
PM
Selkoe
D J
DJ
Romig
H
H
Mendla
K
K
Haass
C
C
D000544:Alzheimer Disease / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis / Q000235:genetics; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D019281:Dimerization; D005786:Gene Expression Regulation; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics* / Q000302:isolation & purification; D008958:Models, Molecular; D009097:Multienzyme Complexes / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry; D053764:Presenilin-1; D046988:Proteasome Endopeptidase Complex; D011499:Protein Processing, Post-Translational; D017433:Protein Structure, Secondary; D014162:Transfection
D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; D009097:Multienzyme Complexes; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex