Mutations

PSEN1 L166P

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Spastic Paraparesis, Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73653577 T>C
dbSNP ID: rs63750265
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CTT to CCT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 6
Research Models: 4

Findings

L166P appears to be a relatively rare mutation associated with a very early age of symptom onset. It was first reported in a woman 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 an individual who developed progressive memory impairment, dysarthria, and spastic paraparesis at age 23 (Lyoo et al., 2016).

Neuropathology

Postmortem examination of the 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).

Biological Effect

When expressed in different types of cultured cells, this mutation impaired the carboxypeptidase-like γ-cleavage, but spared the endoproteolytic ε-cleavage of APP. This resulted in reduced intracellular and secreted levels of Aβ40 and an increased Aβ42/Aβ40 ratio (Bentahir 2006; Koch et al., 2012;Li et al., 2016; Sannerud et al., 2016). An elevated Aβ42/Aβ40 ratio was also reported in neurons derived from induced pluripotent stem cells (iPSCs), which showed decreased total Aβ production and elevated levels of Aβ42 and Aβ43 in culture supernatants (Kwart et al., 2019, Aug 2019 news). In vitro experiments using isolated proteins are consistent with these findings, revealing decreased production of Aβ40, Aβ42, and the APP intracellular domain, and an increased Aβ42/Aβ40 ratio (Winkler et al., 2009; Cacquevel et al., 2012; Sun et al., 2017). The mutation also reduced the endoproteolytic ε-cleavage of N-cadherin and Notch (Moehlmann et al., 2002Bentahir et al., 2006Sannerud et al., 2016). M146V was also shown to promote the accumulation of APP β-C-terminal fragments which disrupt endosomes. 

As assessed by in vitro experiments with isolated proteins, this mutant decreases γ-secretase efficiency by 75 percent for both Notch and APP, reducing global production of Aβ38, Aβ40, Aβ42, and Aβ43 peptides (Chávez-Gutiérrez et al., 2012).  Sizeable reductions in the Aβ38/Aβ42 and Aβ40/Aβ43 ratios were observed, both in cells and in vitro. Interestingly, the levels of the shorter peptides, Aβ40 and Aβ38, were particularly decreased, while those of longer peptides, greater than Aβ42, were increased. These data suggest impairment of the fourth γ-secretase cleavage in the Aβ production lines that sequentially digest Aβ49 and Aβ48 into shorter peptides. A mass spectrometry analysis of the tri- and tetra-peptides released by the mutant revealed decreased activity of the Aβ49 production line in particular (Li et al 2016). 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).

In addition to affecting Aβ peptide production, M146V promotes the accumulation of APP β-C-terminal fragments (β-CTFs) which appears to disrupt endosomes (Kwart et al., 2019, Aug 2019 news). Enlarged endosomes and altered expression of genes involved in endocytic vesicle pathways were observed in iPSC-derived neurons. This phenotype correlated with β-CTF, but not Aβ, levels. 

Insight into how the mutant disrupts PSEN1 conformation has been obtained from fluorescence lifetime imaging microscopy (Berezovska et al., 2005) and Förster resonance energy transfer experiments (Uemura et al., 2009). In addition, a study using APP substrates with photosensitive cross-linkable amino acids revealed the mutant causes mispositioning of the APP C99 cleavage domain (Fukumori and Steiner, 2016). A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates this residue 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).

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). The L166P mutant was also reported to abolish the activity of 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).

 

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: 23 Aug 2019

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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. Familial AD Mutations, β-CTF, Spell Trouble for Endosomes
  2. CryoEM γ-Secretase Structures Nail APP, Notch Binding
  3. 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 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. . 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.
  6. . Effect of Presenilin Mutations on APP Cleavage; Insights into the Pathogenesis of FAD. Front Aging Neurosci. 2016;8:51. Epub 2016 Mar 11 PubMed.
  7. . 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.
  8. . Purification, pharmacological modulation, and biochemical characterization of interactors of endogenous human gamma-secretase. Biochemistry. 2009 Feb 17;48(6):1183-97. PubMed.
  9. . 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.
  10. . 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.
  11. . The mechanism of γ-Secretase dysfunction in familial Alzheimer disease. EMBO J. 2012 May 16;31(10):2261-74. Epub 2012 Apr 13 PubMed.
  12. . Alzheimer's-Causing Mutations Shift Aβ Length by Destabilizing γ-Secretase-Aβn Interactions. Cell. 2017 Jul 27;170(3):443-456.e14. PubMed.
  13. . 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.
  14. . Allosteric modulation of PS1/gamma-secretase conformation correlates with amyloid beta(42/40) ratio. PLoS One. 2009;4(11):e7893. PubMed.
  15. . 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.
  16. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  17. . 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.
  18. . 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.

External Citations

  1. Aug 2019 news

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.

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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