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
Genomic Region: Exon 12
Mutation Type: Point, Missense
Codon Change: CTT to TTT

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).

Biological Effect

Experiments in cell lines have suggested that this presenilin mutation may result in a substantial—or even a complete—loss of γ-secretase activity. Apparent reduced cleavage of multiple γ-secretase substrates, including APP and Notch, has been observed, with minimal production of proteolytic products such as Aβ40, Aβ42, and APP C-terminal fragments (APP-CTFs). The mutant presenilin-1 was appropriately trafficked to the cell surface; however, endoproteolysis of the protein was impaired, which may account for the reduced enzyme activity (Heilig et al., 2010). In a mouse model expressing this mutation, overall Aβ levels were also low, but the Aβ42/Aβ40 ratio was increased and the mouse developed amyloid deposits (Xia et al., 2015Mar 2015 news).

Rather than causing loss of γ-secretase activity, there is evidence that the L435F mutation in PSEN1 may impair the carboxypeptidase-like activity of γ-secretase, altering the enzyme's specificity for APP and favoring the production of Aβ43. Cell lines expressing the L435F mutation produced less Aβ40 and Aβ42, but more Aβ43 (Kretner et al., 2016). However, low levels of Aβ43 were reported in the heterozygous mouse model carrying the mutation (Xia et al., 2016). Differences in model systems or experimental procedures have been proposed to account for this discrepancy (see Apr 2016 news).

Research Models

Heterozygous knock-in 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).

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References

News Citations

  1. Mutant Presenilin Knock-in Mice Mimic Knockouts, Stir Old Debate
  2. Pathogenic Presenilin Mutations Generate Aβ43

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. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
  3. . 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.
  4. . 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.
  5. . Loss of Aβ43 Production Caused by Presenilin-1 Mutations in the Knockin Mouse Brain. Neuron. 2016 Apr 20;90(2):417-22. PubMed.

Further Reading

Papers

  1. . 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.

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

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.

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