Presenilins are aspartyl intramembrane proteases that form the catalytic core of the gamma-secretase complex. In humans, the two principal paralogs are PSEN1 (presenilin-1) and PSEN2 (presenilin-2), both of which are central to amyloid precursor protein (APP) processing and familial Alzheimer's disease biology. Over 300 pathogenic mutations in PSEN1 and PSEN2 have been identified, accounting for the majority of early-onset familial AD cases.
¶ Structure and Function
Presenilins are approximately 450-500 amino acids with:
- Nine transmembrane domains: Embedded in the lipid bilayer
- Two aspartate residues: Located in transmembrane domains 6 and 7, essential for proteolytic activity
- N-terminal and C-terminal fragments: Generated by endoproteolysis
- Pen-2, APH-1, and NCT: Essential co-factors in the gamma-secretase complex
The functional gamma-secretase complex consists of four components:
- Presenilin: The catalytic subunit (PSEN1 or PSEN2)
- Aph-1 (Anterior Pharynx Defective 1): Stabilizes the complex
- Pen-2 (Presenilin Enhancer 2): Required for endoproteolysis and activity
- Nicastrin (NCT): May serve as the substrate receptor
Gamma-secretase performs regulated intramembrane proteolysis (RIP):
- Initial cleavage: APP is cleaved by BACE1 at the beta-site
- Gamma-secretase cleavage: Occurs within the transmembrane domain
- A-beta production: Generates A-beta peptides of varying lengths (A-beta 37-43)
- Notch processing: Gamma-secretase also cleaves Notch receptors
Presenilins are essential for the gamma-secretase cleavage of APP:
- A-beta generation: Produces amyloid-beta peptides
- A-beta 42/43 ratio: Pathogenic mutations increase the longer, more aggregation-prone forms
- Amyloid hypothesis: A-beta production is central to AD pathogenesis
Autosomal dominant mutations in presenilin genes cause early-onset FAD:
- PSEN1 mutations: Over 200 known, onset typically 30-50 years
- PSEN2 mutations: Over 40 known, onset typically 40-70 years
- Penetrance: High, but variable expressivity
- Phenotype variability: Some mutations cause atypical presentations
The most common cause of familial AD:
- Located on chromosome 14q24.3
- Highly expressed in neurons
- Mutations cause severe, early-onset AD
- Associated with cotton-wool plaques and spastic paraparesis
Less common but important:
- Located on chromosome 1q42.13
- Expressed in neurons and other tissues
- Mutations cause variable onset and progression
- Some variants may have reduced penetrance
The field debates whether presenilin mutations cause:
- Loss of gamma-secretase function: Reduced cleavage of substrates
- Gain of toxic function: Altered cleavage products
- Combination: Both mechanisms likely contribute
Gamma-secretase has many substrates beyond APP:
- Notch receptors: Critical for development
- E-cadherin: Cell adhesion
- LDL receptor-related proteins: Lipid metabolism
- Voltage-gated sodium channels: Neuronal excitability
- Synaptic proteins: Synaptic function
- Development challenges: Notch-related toxicity limited clinical use
- A狭特异性抑制剂: MODA, avagacestat
- Notch-sparing inhibitors: In development
- Modulators: Shift cleavage towards shorter A-beta
- NSAIDs: Some reduce A-beta 42 production
- Natural compounds: Flavonoids, polyphenols
- Allosteric modulators: In development
- AAV delivery: Potential for wild-type PSEN1/2
- CRISPR approaches: Future possibility for mutation correction
- RNAi: Knockdown of mutant alleles