title: Expression of Alzheimer's disease-associated presenilin-1 is controlled by proteolytic degradation and complex formation.
abstract: 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.
authors.affiliation: Central Institute of Mental Health, Department of Molecular Biology, J5, 68159 Mannheim, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Steiner
authors.forename: A
authors.initials: A
authors.lastname: Capell
authors.forename: B
authors.initials: B
authors.lastname: Pesold
authors.forename: M
authors.initials: M
authors.lastname: Citron
authors.forename: P M
authors.initials: PM
authors.lastname: Kloetzel
authors.forename: D J
authors.initials: DJ
authors.lastname: Selkoe
authors.forename: H
authors.initials: H
authors.lastname: Romig
authors.forename: K
authors.initials: K
authors.lastname: Mendla
authors.forename: C
authors.initials: C
authors.lastname: Haass
mesh_terms: 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
chemical_list: 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