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Published on: October 17, 2015
The pathogenicity of PSEN2 variants is tied to Aβ production and homology to PSEN1
Lei Liu1,2, Stephanie A Schultz2,3, Adriana Saba1
1Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Introduction:
Though recognized as a potential cause of autosomal dominant Alzheimer's disease, the pathogenicity of many PSEN2 variants remains uncertain. We compared amyloid beta (Aβ) production across all missense PSEN2 variants in the AlzForum database and, when possible, to corresponding PSEN1 variants.
Methods:
We expressed 74 PSEN2 variants, 21 of which had known, homologous PSEN1 pathogenic variants with the same amino acid substitution, in HEK293 cells lacking presenilin 1/2. Aβ production was compared to age at symptom onset (AAO) and between PSEN1/2 homologs.
Results:
Aβ42/40 and Aβ37/42 ratios correlated with AAO across all PSEN2 variants, strongly driven by the subset of PSEN2 variants with PSEN1 homologs. Aβ production across PSEN1/2 homologs was highly correlated. PSEN2 AAO correlated with AAO in PSEN1 homologs but was an average of 18.3 years later.
Discussion:
The existence of a PSEN1 homolog and patterns of Aβ production are important considerations in assessing the pathogenicity of previously reported and new PSEN2 variants.
Highlights:
There were associations between the patterns of amyloid beta (Aβ) production across presenilin 2 (PSEN2) variants and age at symptom onset (AAO). PSEN2 variants for which there is a known, corresponding variant in presenilin 1 (PSEN1) are more likely to have abnormal Aβ production patterns that strongly correlate with AAO, compared to those that lack a known PSEN1 counterpart ("non-homologous PSEN2 variants"). Most PSEN2 variants lacking PSEN1 counterparts had Aβ42/40 ratios close to those of wild-type PSN2, arguing against their pathogenicity. Homologous PSEN1 and PSEN2 variants had correlated Aβ42/40 and Aβ37/42 ratios, indicating that the corresponding amino acid substitution in each presenilin may have largely similar biochemical effects on γ-secretase processivity.
Insights
Assessing the pathogenicity of presenilin 2 (PSEN2) variants is crucial for understanding autosomal dominant Alzheimer's disease. This study reveals that PSEN2 variants with known presenilin 1 (PSEN1) counterparts exhibit distinct amyloid beta production patterns linked to disease onset.
Area of Science:
- Neuroscience and Genetics
- Molecular Biology and Biochemistry
Background:
- Autosomal dominant Alzheimer's disease (ADAD) is linked to mutations in presenilin genes, but the pathogenicity of many PSEN2 variants remains unclear.
- Amyloid beta (Aβ) production is a key factor in Alzheimer's pathogenesis, and its alteration by PSEN2 variants needs further investigation.
Purpose of the Study:
- To compare amyloid beta (Aβ) production across all missense PSEN2 variants.
- To evaluate the correlation between Aβ production patterns and age at symptom onset (AAO).
- To assess the influence of homologous PSEN1 variants on PSEN2 variant pathogenicity.
Main Methods:
- Expressed 74 PSEN2 variants in HEK293 cells lacking endogenous presenilin 1/2.
- Compared Aβ production (Aβ42/40 and Aβ37/42 ratios) for PSEN2 variants, including 21 with known homologous PSEN1 variants.
- Correlated Aβ production with AAO and compared Aβ production between PSEN1/2 homologs.
Main Results:
- Aβ42/40 and Aβ37/42 ratios correlated with AAO across all PSEN2 variants, particularly those with PSEN1 homologs.
- Aβ production patterns were highly correlated between homologous PSEN1 and PSEN2 variants.
- PSEN2 variants lacking PSEN1 counterparts generally showed wild-type-like Aβ production, suggesting lower pathogenicity.
Conclusions:
- The presence of a PSEN1 homolog and specific Aβ production patterns are critical for assessing PSEN2 variant pathogenicity.
- Homologous PSEN1 and PSEN2 variants exhibit similar biochemical effects on γ-secretase activity, influencing Aβ processing.
- This comparative analysis aids in the clinical interpretation of both known and novel PSEN2 variants associated with ADAD.
