Mutations

PSEN1 L435F

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73685896 C>T
dbSNP ID: rs63750001
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CTT to TTT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 12
Research Models: 1

Findings

This mutation was first reported in one out of 414 people with suspected Alzheimer's disease. However, no clinical, neuropathological, or family details were reported (Rogaeva et al., 2001).

The L435F mutation was subsequently identified in two siblings with a family history of early onset AD (Heilig et al., 2010). The reported pedigree shows a third affected sibling, as well as their affected father. The average age of onset was 47 years, and the average age at death was 56 years. Disease in this family presented as early and progressive memory problems and aphasia. Motor symptoms, including parkinsonism, developed later, but not spastic paraparesis. Segregation with disease was suggested by the fact that the mutation was found in both of the affected siblings tested.

Neuropathology

Neuropathological analysis of the two affected mutation carriers showed numerous and widespread cotton-wool plaques throughout the neocortex, hippocampus, and deep cerebral nuclei. These large plaques lacked a dense core and were associated with neuritic dystrophy. Some neurofibrillary tangles were observed in the cortex, with high concentrations in the entorhinal cortex and hippocampus. Evidence of mild cerebral amyloid angiopathy was present in vessels. The substantia nigra was affected by neuronal loss, depigmentation, and gliosis (Heilig et al., 2010). The plaques in the frontal cortex and hippocampus contained Aβ40 and Aβ42, but also substantially more Aβ43 relative to plaques in AD patients without the L435F mutation (Kretner et al., 2016). Strong Aβ43 staining was also reported in the brain of another L435F mutation carrier (Oakley et al., 2020).

Biological Effect

Observations in patient brains, cell lines, rodent models, and in vitro experiments have shown this mutation disrupts the proteolytic processing of APP and Notch-1. Of particular interest, L435F has been reported to increase levels of Aβ43, an aggregating and neurotoxic peptide (Kretner et al., 2016; Veugelen et al., 2016; April 2016 newsTambini and D'Adamio, 2020, Oakley et al., 2020). Initial findings suggested it drastically reduces levels of Aβ40, Aβ42, the APP C-terminal fragment, and the Notch-1 intracellular domain (Heilig et al., 2010; Sun et al., 2017), which was considered supportive of the hypothesis that loss of presenilin function plays an important role in at least some cases of familial AD pathogenesis. Indeed, in a heterozygous L435F knockin mouse, Xia and colleagues found decreased levels of Aβ40 and Aβ42 (Xia et al., 2015; Mar 2015 news). However, subsequent studies in cells (Kretner et al., 2016; Veugelen et al., 2016; April 2016 news), including neurons derived from induced pluripotent stem cells (iPSCs) from a mutation carrier (Oakley et al., 2020), and in human brain tissue (Kretner et al., 2016; Oakley et al., 2020), revealed the mutation increases levels of Aβ43. In addition, although decreased levels of Aβ43 were reported in heterozygous knockin mice (Xia et al., 2016), the peptide was found to be elevated in both heterozygous and homozygous knockin rats (Tambini and D'Adamio, 2020). Of note, in the iPSC-derived neurons, soluble Aβ40 and Aβ42 were similar to controls (Oakley et al., 2020). 

Assays using purified PSEN1 complexes and a tagged APPC99 substrate revealed PSEN1 L435F is more sensitive to increased temperatures than wildtype PSEN1, suggesting the mutation destabilizes the interaction required for proteolysis of APPC99 and newly produced Aβn substrates, resulting in the release of longer Aβ peptides (Szaruga et al., 2017). This alteration may contribute to the observed increase in Aβ43 production.

The mutation also seems to affect PSEN1 function by nearly abrogating autoproteolysis (Sun et al., 2017). Moreover, a dominant-negative effect on wild-type PSEN1 may also contribute to its pathogenecity. Experiments using cultured cells and isolated proteins revealed the mutant alters production of Aβ peptides by wild-type presenilin, an effect that was differentially sensitive to detergents suggesting inhibition through hetero-oligomerization (Heilig et al., 2013Zhou et al., 2017). 

L435 has been shown to directly interact with APP, forming part of the PAL motif implicated in the recognition of APP by γ-secretase (Sato et al., 2008; Zhou et al., 2019; Jan 2019 news). 

Research Models

Heterozygous knockin mice carrying human presenilin-1 with the L435F mutation develop deficits in synaptic plasticity and memory as well as age-related neurodegeneration. The mutant presenilin-1 led to perinatal lethality in homozygous mice (Xia et al., 2015). In rats, however, knockin homozygosity is not lethal and the animals survive to adulthood, expressing low levels of Aβ38, Aβ40, and Aβ42, but high levels Aβ43 (Tambini and D'Adamio, 2020). Also, induced pluripotent stem cell (iPSC) lines have been generated from mutation carrier cells and differentiated into neurons (Oakley et al., 2020). When compared to iPSC-derived neurons from  non-carriers, these cells produced similar levels of soluble Aβ40 and Aβ42, but high levels of Aβ43.

Last Updated: 12 May 2020

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

News Citations

  1. Pathogenic Presenilin Mutations Generate Aβ43
  2. Mutant Presenilin Knock-in Mice Mimic Knockouts, Stir Old Debate
  3. CryoEM γ-Secretase Structures Nail APP, Notch Binding

Paper Citations

  1. . Presenilin-1 knockin mice reveal loss-of-function mechanism for familial Alzheimer's disease. Neuron. 2015 Mar 4;85(5):967-81. PubMed.
  2. . Knock-in rats with homozygous PSEN1L435F Alzheimer mutation are viable and show selective γ-secretase activity loss causing low Aβ40/42 and high Aβ43. J Biol Chem. 2020 May 22;295(21):7442-7451. Epub 2020 Apr 7 PubMed.
  3. . The Alzheimer Disease-Causing Presenilin-1 L435F Mutation Causes Increased Production of Soluble Aβ43 Species in Patient-Derived iPSC-Neurons, Closely Mimicking Matched Patient Brain Tissue. J Neuropathol Exp Neurol. 2020 Jun 1;79(6):592-604. PubMed.
  4. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
  5. . A presenilin-1 mutation identified in familial Alzheimer disease with cotton wool plaques causes a nearly complete loss of gamma-secretase activity. J Biol Chem. 2010 Jul 16;285(29):22350-9. PubMed.
  6. . Generation and deposition of Aβ43 by the virtually inactive presenilin-1 L435F mutant contradicts the presenilin loss-of-function hypothesis of Alzheimer's disease. EMBO Mol Med. 2016 May 2;8(5):458-65. PubMed.
  7. . Familial Alzheimer's Disease Mutations in Presenilin Generate Amyloidogenic Aβ Peptide Seeds. Neuron. 2016 Apr 20;90(2):410-6. PubMed.
  8. . Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 PubMed.
  9. . Loss of Aβ43 Production Caused by Presenilin-1 Mutations in the Knockin Mouse Brain. Neuron. 2016 Apr 20;90(2):417-22. PubMed.
  10. . Alzheimer's-Causing Mutations Shift Aβ Length by Destabilizing γ-Secretase-Aβn Interactions. Cell. 2017 Jul 27;170(3):443-456.e14. PubMed.
  11. . Trans-dominant negative effects of pathogenic PSEN1 mutations on γ-secretase activity and Aβ production. J Neurosci. 2013 Jul 10;33(28):11606-17. PubMed.
  12. . Dominant negative effect of the loss-of-function γ-secretase mutants on the wild-type enzyme through heterooligomerization. Proc Natl Acad Sci U S A. 2017 Nov 28;114(48):12731-12736. Epub 2017 Oct 9 PubMed.
  13. . The C-terminal PAL motif and transmembrane domain 9 of presenilin 1 are involved in the formation of the catalytic pore of the gamma-secretase. J Neurosci. 2008 Jun 11;28(24):6264-71. PubMed.
  14. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.

Further Reading

Papers

  1. . Quantifying correlations between mutational sites in the catalytic subunit of γ-secretase. J Mol Graph Model. 2019 May;88:221-227. Epub 2019 Feb 8 PubMed.

Protein Diagram

Primary Papers

  1. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.

Alzpedia

Disclaimer: Alzforum does not provide medical advice. The Content is for informational, educational, research and reference purposes only and is not intended to substitute for professional medical advice, diagnosis or treatment. Always seek advice from a qualified physician or health care professional about any medical concern, and do not disregard professional medical advice because of anything you may read on Alzforum.