Mutations

PSEN1 G384A

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73683855 G>C
dbSNP ID: rs63750646
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GGA to GCA
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 11

Findings

This mutation was first identified by linkage analysis in a large Belgian family affected by early onset Alzheimer’s disease (Cruts et al., 1995). The family, known as AD/B, included at least 16 affected individuals over five generations. The average age of onset was 35 (34.7 ± 3.0 years). The diagnosis of AD was confirmed in several family members at autopsy. Clinical information related to this family was reported in Martin et al., 1991.

A Japanese family with this mutation has also been identified (Tanahashi et al., 1996). This family, known as FAD-Yg, included four family members affected by early onset AD. Symptom onset ranged from 31 to 37 years old. Two family members had postmortem confirmed AD.

Neuropathology

Neuropathology consistent with AD was observed in members of the AD/B family. In addition to typical AD pathology of cortical plaques and tangles, amyloid plaques were also noted in the cerebellum. Typical AD pathology was observed in at least two members of the FAD-Yg family from Japan (Tanahashi et al., 1996).

Biological Effect

This mutation has been reported to impair the carboxypeptidase-like γ-cleavage, but spare the endoproteolytic ε-cleavage activity of PSEN1 (Li et al., 2016; Murayama et al., 1997). As assessed by in vitro experiments with isolated proteins, it decreases γ-secretase efficiency by 75 percent for both Notch and APP (Chávez-Gutiérrez et al., 2012). Cell-based and in vitro experiments indicate it reduces production of Aβ40, while increasing Aβ42, resulting in an elevated Aβ42/Aβ40 ratio (DeJonghe et al., 1999; Bentahir et al., 2006; Li et al. 2016; Sun et al., 2017).

Experiments with isolated proteins revealed the mutant appears to slow Aβ40, but not Aβ42, production (Fluhrer et at., 2008). Moreover, two groups observed sizeable reductions in the Aβ38/Aβ42 and Aβ40/Aβ43 ratios, both in cells and in vitro (Chávez-Gutiérrez et al., 2012; Svedružić et al., 2012). 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 study using mass spectrometry to monitor the tri- and tetra-peptides released by HEK293 cells stably expressing Swedish mtAPP695 and BACE1, and transfected with the PSEN1 G384A mutant, indicated that, indeed, both production lines are disrupted (Li et al., 2016).

Moreover, in vitro assays revealed that mutant γ-secretase activity is more sensitive to increased temperatures than the wild-type protein, suggesting the mutation destabilizes the enzyme-substrate interaction required for sequential Aβ peptide proteolysis, resulting in the release of longer Aβ peptides (Szaruga et al., 2017; Jul 2017 news). A conformational change that affects how the APP substrate is presented to the active site of γ-secretase has been observed using fluorescence lifetime imaging microscopy (Berezovska et al., 2005). Interestingly, two suppressor mutations identified in a yeast model system activated Aβ trimming and reduced Aβ42 production in mouse fibroblasts expressing PSEN1 G384A (Futai et al., 2016).

G384 has been implicated in the interaction of γ-secretase with both APP and Notch. The amide group of G384 appears to donate a conserved H-bond to anchor the transmembrane helix of each substrate (Zhou et al., 2019; Yang et al., 2019; Jan 2019 news).

Additionally, this mutation caused PSEN1 to localize to endolysosomal compartments, similar to the distribution of PSEN2. This resulted in altered substrate specificity and an increased Aβ42/Aβ40 ratio in the intracellular pool of Aβ (Sannerud et al., 2016; see May 2016 news).

The G384A mutation may also affect other cellular functions. For example, it was reported to abolish the activity of a calcium leak channel in the endoplasmic reticulum in patient fibroblasts (Nelson et al., 2007).

Last Updated: 12 Aug 2019

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References

News Citations

  1. sAPP Binds GABA Receptor, and More News on APP
  2. CryoEM γ-Secretase Structures Nail APP, Notch Binding
  3. Lodged in Late Endosomes, Presenilin 2 Churns Out Intraneuronal Aβ

Paper Citations

  1. . Molecular genetic analysis of familial early-onset Alzheimer's disease linked to chromosome 14q24.3. Hum Mol Genet. 1995 Dec;4(12):2363-71. PubMed.
  2. . Early-onset Alzheimer's disease in 2 large Belgian families. Neurology. 1991 Jan;41(1):62-8. PubMed.
  3. . Sequence analysis of presenilin-1 gene mutation in Japanese Alzheimer's disease patients. Neurosci Lett. 1996 Nov 1;218(2):139-41. PubMed.
  4. . Effect of Presenilin Mutations on APP Cleavage; Insights into the Pathogenesis of FAD. Front Aging Neurosci. 2016;8:51. Epub 2016 Mar 11 PubMed.
  5. . Different effects of Alzheimer-associated mutations of presenilin 1 on its processing. Neurosci Lett. 1997 Jun 20;229(1):61-4. PubMed.
  6. . The mechanism of γ-Secretase dysfunction in familial Alzheimer disease. EMBO J. 2012 May 16;31(10):2261-74. Epub 2012 Apr 13 PubMed.
  7. . Evidence that Abeta42 plasma levels in presenilin-1 mutation carriers do not allow for prediction of their clinical phenotype. Neurobiol Dis. 1999 Aug;6(4):280-7. PubMed.
  8. . Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms. J Neurochem. 2006 Feb;96(3):732-42. PubMed.
  9. . 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.
  10. . Intramembrane proteolysis of GXGD-type aspartyl proteases is slowed by a familial Alzheimer disease-like mutation. J Biol Chem. 2008 Oct 31;283(44):30121-8. PubMed.
  11. . Modulation of γ-secretase activity by multiple enzyme-substrate interactions: implications in pathogenesis of Alzheimer's disease. PLoS One. 2012;7(3):e32293. 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. . 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.
  15. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  16. . Structural basis of Notch recognition by human γ-secretase. Nature. 2019 Jan;565(7738):192-197. Epub 2018 Dec 31 PubMed.
  17. . 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.
  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.

Further Reading

Papers

  1. . Familial Alzheimer's disease genes in Japanese. J Neurol Sci. 1998 Sep 18;160(1):76-81. PubMed.
  2. . Decrease in catalytic capacity of γ-secretase can facilitate pathogenesis in sporadic and Familial Alzheimer's disease. Mol Cell Neurosci. 2015 Jul;67:55-65. Epub 2015 Jun 4 PubMed.
  3. . Intracellular Accumulation of Toxic Turn Amyloid-β is Associated with Endoplasmic Reticulum Stress in Alzheimer's disease. Curr Alzheimer Res. 2012 Aug 30; PubMed.
  4. . Abnormal cross-talk between mutant presenilin 1 (I143T, G384A) and glycosphingolipid biosynthesis. FASEB J. 2012 Jul;26(7):3065-74. PubMed.
  5. . Presenilin-1 but not amyloid precursor protein mutations present in mouse models of Alzheimer's disease attenuate the response of cultured cells to γ-secretase modulators regardless of their potency and structure. J Neurochem. 2011 Feb;116(3):385-95. PubMed.
  6. . Increase in p53 protein levels by presenilin 1 gene mutations and its inhibition by secretase inhibitors. J Alzheimers Dis. 2009;16(3):565-75. PubMed.
  7. . Enhancement of activation of caspases by presenilin 1 gene mutations and its inhibition by secretase inhibitors. J Alzheimers Dis. 2009;16(3):551-64. PubMed.
  8. . DAPT-induced intracellular accumulations of longer amyloid beta-proteins: further implications for the mechanism of intramembrane cleavage by gamma-secretase. Biochemistry. 2006 Mar 28;45(12):3952-60. PubMed.
  9. . BACE1 and mutated presenilin-1 differently modulate Abeta40 and Abeta42 levels and cerebral amyloidosis in APPDutch transgenic mice. Neurodegener Dis. 2007;4(2-3):127-35. PubMed.
  10. . Distinct mechanisms by mutant presenilin 1 and 2 leading to increased intracellular levels of amyloid beta-protein 42 in Chinese hamster ovary cells. Biochemistry. 2003 Feb 4;42(4):1042-52. PubMed.
  11. . Immunoreactivity of presenilin-1 and tau in Alzheimer's disease brain. Exp Neurol. 1998 Feb;149(2):341-8. PubMed.
  12. . Proteolytic processing of presenilin-1 in human lymphoblasts is not affected by the presence of the I143T and G384A mutations. Neurosci Lett. 1999 Oct 29;274(3):183-6. PubMed.

Learn More

  1. Japanese Familial Alzheimer's Disease Database

Protein Diagram

Primary Papers

  1. . Molecular genetic analysis of familial early-onset Alzheimer's disease linked to chromosome 14q24.3. Hum Mol Genet. 1995 Dec;4(12):2363-71. PubMed.
  2. . Sequence analysis of presenilin-1 gene mutation in Japanese Alzheimer's disease patients. Neurosci Lett. 1996 Nov 1;218(2):139-41. PubMed.

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