Mutations

PSEN1 L166P

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic, ALS-FTD : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PM6, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Spastic Paraparesis
Reference Assembly: GRCh37/hg19
Position: Chr14:73653577 T>C
dbSNP ID: rs63750265
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CTT to CCT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 6
Research Models: 4

Findings

This mutation is associated with very early disease onset and a variable phenotype. It was first reported in a woman with familial Alzheimer's disease (AD) who developed secondary generalized seizures at age 15, major depression at age 19, and memory impairment by age 24. Ataxia and spastic paraparesis were recorded by age 27, and moderate-stage dementia by 28. Dementia, ataxia, and spasticity progressed until death at age 35. Family history details were not reported (Moehlmann et al., 2002). The mutation was also found in a Korean man who developed a variant of AD with progressive memory impairment, dysarthria, and spastic paraparesis at age 23 (Lyoo et al., 2016). The mutation was suspected to have arisen de novo, although paternity was not confirmed. 

In addition, this variant was reported in three members of a family with primary lateral sclerosis (PLS), a progressive upper motor disorder sometimes classified as a form of amyotrophic lateral sclerosis (ALS) (Vázquez-Costa et al., 2021). Mild cognitive and behavioral symptoms appeared years after the motor symptoms. The proband progressed toward akinetic mutism, suggesting that severe dementia might appear late in the disease course. Both of the proband's children were affected, but his parents were healthy, suggesting the mutation might have arisen de novo in the proband. The father was not genotyped, however. 

The variant was absent from the gnomAD variant database (gnomAD v2.1.1, June 2021).

Neuropathology

Postmortem examination of the original proband’s brain revealed numerous Aβ-positive neuritic and cotton-wool plaques throughout the cerebral cortex. Aβ-positive amyloid cores were abundant in the cerebellar cortex (Moehlmann et al., 2002). In the second individual, robust amyloid pathology was observed in the striatum and cerebellum, and asymmetric tau pathology in the primary sensorimotor cortex contralateral to the side most affected by spasticity (Lyoo et al., 2016).

In one patient with PLS, FDG-PET showed hypometabolism in both anterior temporal lobes, pre- and post-central gyri, and cerebellum, a pattern that was not characteristic of either AD or PLS (Vázquez-Costa et al., 2021). MRI revealed microbleeds suggestive of amyloid angiopathy. Of note, 18F-flutemetamol PET showed widespread amyloid deposition in the brain, except in hypometabolic areas, suggesting amyloid may not be responsible for the observed symptoms.

Biological Effect

This variant has long been known to increase the well-established biomarker of AD, the Aβ42/Aβ40 ratio, both in cultured cells (e.g., Bentahir 2006; Chávez-Gutiérrez et al., 2012Koch et al., 2012Li et al., 2016; Sannerud et al., 2016) and in vitro assays using isolated proteins (Winkler et al., 2009; Chávez-Gutiérrez et al., 2012Cacquevel et al., 2012; Sun et al., 2017). More recently, it has been reported to reduce Aβ (37 + 38 + 40) / (42 + 43) and Aβ37/Aβ42, two ratios reported to outperform the Aβ42/Aβ40 ratio as indicators of AD pathogenicity, with the former correlating with AD age at onset (Apr 2022 news; Petit et al., 2022; Liu et al., 2022).

Multiple factors have been proposed to contribute to L166P's pathogenicity. Aβ42 is a well-known component of amyloid plaques, but other, longer peptides, in particular Aβ43, are also toxic and may be equally or more important in mediating this variant’s harmful effects (Trambauer et al., 2020, Kakuda et al., 2021). Moreover, L166P promotes the accumulation of APP β-C-terminal fragments (β-CTFs) which disrupt endosomes (Kwart et al., 2019, Aug 2019 news). Enlarged endosomes and altered expression of genes involved in endocytic vesicle pathways were observed in neurons derived from induced pluripotent stem cells (iPSCs) generated from carrier cells. Interestingly, this phenotype correlated with β-CTF, but not Aβ, levels. Also, L166P appears to stall the γ-secretase-substrate complex and the presence of this membrane-anchored complex per se, rather than the release of Aβ peptides, correlates with synaptic loss in transgenic C. elegans neurons (Devkota et al., 2024; Nov 2023 news).

L166P drastically reduces ε-cleavage of PSEN1, as well as of Notch and N-cadherin (Moehlmann et al., 2002Bentahir et al., 2006Chávez-Gutiérrez et al., 2012; Do et al., 2023; Devkota et al., 2024). One of the first detailed examinations of how L166P disrupts APP processing further indicated that this variant impairs PSEN1 carboxypeptidase-like trimming activity, particularly the fourth γ-secretase cleavage that digests Aβ43 to Aβ40 in the Aβ48 pathway and Aβ42 to Aβ38 in the Aβ49 pathway (Chávez-Gutiérrez et al., 2012).  Moreover, in vitro experiments testing the mutant’s γ-secretase activity at different temperatures showed it increases enzyme-Aβn complex dissociation rates, enhancing the release of longer Aβ peptides (Szaruga et al., 2017). Reduction in earlier cleavage events has been suggested by a study showing deficient Aβ48→Aβ45 and Aβ46→Aβ43 trimming (Devkota et al., 2024).

Insights into the structural underpinnings of these disruptions have been obtained from fluorescence lifetime imaging microscopy (Berezovska et al., 2005) and Förster resonance energy transfer experiments (Uemura et al., 2009). In addition, studies using APP substrates with photosensitive cross-linkable amino acids revealed the mutant causes mispositioning of the APP C99 cleavage domain (Fukumori and Steiner, 2016; Trambauer et al., 2020). In particular, altered cross-linking at T48 and L49, the initial substrate cleavage sites of C99, was observed. The authors suggested this could affect interactions whose strengths play a key role in the carboxy‐terminal trimming pathway and the generation of pathogenic longer Aβ species.

Moreover, molecular dynamics simulations suggested L166P lengthens the distance between the two catalytic aspartates, D257 and D385, limiting their ability to trap a water molecule for ε-cleavage of APP (Do et al., 2023). This study also noted the mutation may restrict APP access to the PSEN1 active site.

Cryo-electron microscopy studies have also yielded clues to L166P’s toxicity. A study of γ-secretase bound to an APP fragment indicated L166 is apposed to the APP transmembrane helix, with its side-chain reaching towards the interior of the substrate-binding pore (Zhou et al., 2019; Jan 2019 news). More recently, molecular dynamics simulations based on cryo-EM data of γ-secretase trapped in a catalytic transition state have suggested L166P, along with other familial AD pathogenic mutations, binds more tightly to the substrate than wildtype PSEN1 (Devkota et al., 2024, Nov 2023 news). This altered binding appears to limit the active site's conformational flexibility and slows catalysis.

PSEN1 L166P may also have a dominant-negative effect on wild-type PSEN1 as suggested by the suppression of Aβ production by wild-type PSEN1 in the presence of the mutant protein in vitro. The effect was specifically sensitive to a detergent that disrupts PSEN1 oligomerization, indicating the mutant may disrupt wild-type activity via hetero-oligomerization (Zhou et al., 2017).

Furthermore, L166P may disrupt other cellular functions relevant to AD. For example, as reported in a preprint, L166P reduced the interaction of PSEN1 with the glutamate transporter GLT-1, an alteration that may impair GLT-1 homo-oligomerization and its transport to the cell surface (Perrin et al., 2023). PSEN1 has also been reported to play a role in ApoE secretion and cytosolic localization. In experiments with PSEN-deficient fibroblasts, L166P transfection was less able to rescue these functions compared with transfection of wildtype PSEN1 (Islam et al., 2022). This mutant was also reported to abolish PSEN1's activity as a calcium leak channel in the endoplasmic reticulum (Nelson et al., 2007), and caused PSEN1 to localize to endolysosomal compartments, similar to the distribution of PSEN2 (Sannerud et al., 2016; see May 2016 news).

Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Xiao et al., 2021).

Pathogenicity

Alzheimer's Disease : Pathogenic

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

PS3-S

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

PM1-S

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. L166P: Variant is in a mutational hot spot and cryo-EM data suggest residue is of functional importance.

PM2-M

Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.

PM5-M

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

PM6-M

Assumed de novo, but without confirmation of paternity and maternity.

PP2-P

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

PP3-P

Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). *In most cases, Alzforum applies this criterion when the variant’s PHRED-scaled CADD score is greater than or equal to 20.

Pathogenic (PS, PM, PP) Benign (BA, BS, BP)
Criteria Weighting Strong (-S) Moderate (-M) Supporting (-P) Supporting (-P) Strong (-S) Strongest (BA)

Research Models

This mutation has been introduced into mouse models including the double transgenic model, APPPS1, which also expresses APP with the Swedish mutation, and the APP+PS1 transgenic rat, which expresses human APP with the Swedish and Indiana mutations. In addition, the mutation has been inserted in mice expressing the APP Swedish mutation and lacking the Trem2 gene, Trem2 KO (KOMP) x APPPS1, as well as in mice expressing the APP Swedish mutation and a R47H variant of the Trem2 gene, Trem2 R47H KI (Lamb/Landreth) X APPPS1-21.

An iPSC line carrying this mutation has been created using CRISPR technology (Kwart et al., 2019). It is part of a collection of isogenic iPSCs carrying familial AD mutations.

Last Updated: 14 Feb 2024

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References

Research Models Citations

  1. APPPS1
  2. APP+PS1
  3. Trem2 KO (KOMP) x APPPS1
  4. Trem2 R47H KI (Lamb/Landreth) X APPPS1-21

News Citations

  1. Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40?
  2. Familial AD Mutations, β-CTF, Spell Trouble for Endosomes
  3. Patricidal Protein? Aβ42 said to Inhibit Its Parent, γ-Secretase
  4. CryoEM γ-Secretase Structures Nail APP, Notch Binding
  5. Lodged in Late Endosomes, Presenilin 2 Churns Out Intraneuronal Aβ

Paper Citations

  1. . A Large Panel of Isogenic APP and PSEN1 Mutant Human iPSC Neurons Reveals Shared Endosomal Abnormalities Mediated by APP β-CTFs, Not Aβ. Neuron. 2019 Oct 23;104(2):256-270.e5. Epub 2019 Aug 12 PubMed.
  2. . Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Abeta 42 production. Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):8025-30. PubMed.
  3. . Tau Accumulation in Primary Motor Cortex of Variant Alzheimer's Disease with Spastic Paraparesis. J Alzheimers Dis. 2016;51(3):671-5. PubMed.
  4. . Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms. J Neurochem. 2006 Feb;96(3):732-42. PubMed.
  5. . The mechanism of γ-Secretase dysfunction in familial Alzheimer disease. EMBO J. 2012 May 16;31(10):2261-74. Epub 2012 Apr 13 PubMed.
  6. . Presenilin-1 L166P mutant human pluripotent stem cell-derived neurons exhibit partial loss of γ-secretase activity in endogenous amyloid-β generation. Am J Pathol. 2012 Jun;180(6):2404-16. PubMed.
  7. . Effect of Presenilin Mutations on APP Cleavage; Insights into the Pathogenesis of FAD. Front Aging Neurosci. 2016;8:51. Epub 2016 Mar 11 PubMed.
  8. . Restricted Location of PSEN2/γ-Secretase Determines Substrate Specificity and Generates an Intracellular Aβ Pool. Cell. 2016 Jun 30;166(1):193-208. Epub 2016 Jun 9 PubMed.
  9. . Purification, pharmacological modulation, and biochemical characterization of interactors of endogenous human gamma-secretase. Biochemistry. 2009 Feb 17;48(6):1183-97. PubMed.
  10. . Alzheimer's disease-linked mutations in presenilin-1 result in a drastic loss of activity in purified γ-secretase complexes. PLoS One. 2012;7(4):e35133. PubMed.
  11. . 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.
  12. . Aβ profiles generated by Alzheimer's disease causing PSEN1 variants determine the pathogenicity of the mutation and predict age at disease onset. Mol Psychiatry. 2022 Jun;27(6):2821-2832. Epub 2022 Apr 1 PubMed.
  13. . Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease. Alzheimers Dement. 2022 Mar 12; PubMed.
  14. . Aβ43-producing PS1 FAD mutants cause altered substrate interactions and respond to γ-secretase modulation. EMBO Rep. 2020 Jan 7;21(1):e47996. Epub 2019 Nov 25 PubMed.
  15. . Switched Aβ43 generation in familial Alzheimer's disease with presenilin 1 mutation. Transl Psychiatry. 2021 Nov 3;11(1):558. PubMed.
  16. . Familial Alzheimer mutations stabilize synaptotoxic γ-secretase-substrate complexes. Cell Rep. 2024 Feb 12;43(2):113761. PubMed.
  17. . Effects of presenilin-1 familial Alzheimer's disease mutations on γ-secretase activation for cleavage of amyloid precursor protein. Commun Biol. 2023 Feb 14;6(1):174. PubMed.
  18. . Alzheimer's-Causing Mutations Shift Aβ Length by Destabilizing γ-Secretase-Aβn Interactions. Cell. 2017 Jul 27;170(3):443-456.e14. PubMed. Correction.
  19. . Familial Alzheimer's disease presenilin 1 mutations cause alterations in the conformation of presenilin and interactions with amyloid precursor protein. J Neurosci. 2005 Mar 16;25(11):3009-17. PubMed.
  20. . Allosteric modulation of PS1/gamma-secretase conformation correlates with amyloid beta(42/40) ratio. PLoS One. 2009;4(11):e7893. PubMed.
  21. . Substrate recruitment of γ-secretase and mechanism of clinical presenilin mutations revealed by photoaffinity mapping. EMBO J. 2016 Aug 1;35(15):1628-43. Epub 2016 May 23 PubMed.
  22. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  23. . 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.
  24. . Familial Alzheimer disease-linked mutations specifically disrupt Ca2+ leak function of presenilin 1. J Clin Invest. 2007 May;117(5):1230-9. Epub 2007 Apr 12 PubMed.
  25. . APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.

External Citations

  1. gnomAD v2.1.1
  2. Islam et al., 2022

Further Reading

Papers

  1. . Genetic mutations associated with presenile dementia. Neurobiol Aging. 2002 Jul-Aug; 23(S1):322.
  2. . Convergence of pathology in dementia with Lewy bodies and Alzheimer's disease: a role for the novel interaction of alpha-synuclein and presenilin 1 in disease. Brain. 2014 Jul;137(Pt 7):1958-70. Epub 2014 May 24 PubMed.
  3. . Insensitivity to Abeta42-lowering nonsteroidal anti-inflammatory drugs and gamma-secretase inhibitors is common among aggressive presenilin-1 mutations. J Biol Chem. 2007 Aug 24;282(34):24504-13. PubMed.
  4. . Suppressor Mutations for Presenilin 1 Familial Alzheimer Disease Mutants Modulate γ-Secretase Activities. J Biol Chem. 2016 Jan 1;291(1):435-46. Epub 2015 Nov 11 PubMed.
  5. . Membrane lipid remodeling modulates γ-secretase processivity. J Biol Chem. 2023 Apr;299(4):103027. Epub 2023 Feb 16 PubMed.
  6. . APP substrate ectodomain defines amyloid-β peptide length by restraining γ-secretase processivity and facilitating product release. EMBO J. 2023 Dec 1;42(23):e114372. Epub 2023 Oct 18 PubMed.

Protein Diagram

Primary Papers

  1. . Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Abeta 42 production. Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):8025-30. PubMed.

Other mutations at this position

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