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From EST to structure models for functional inference of APP, BACE1, PSEN1, PSEN2 genes.

ABSTRACT: Successive oxidative stress and biochemical changes results in neuronal death and neuritic plaques growth in Alzheimer's disease (AD). Therefore, it is interest to analyze amyloid-?eta precursor protein (APP), beta-secretase 1 (BACE1), presenilin (PSEN1 and PSEN2) genes from brain tissues to gain insights. Development of potential inhibitors for these targets is of significance. EST sequences of 2898 (APP), 539 (BACE1), 786 (PSEN1) and 314 (PSEN2) genes were analyzed in this study. A contig sequences with APP (contigs 1-4), BACE1 (contigs 5-7), PSEN1 (contigs 8, 9, 10, 11), PSEN2 (contigs 13, 14) except PSEN1 (contigs 10) and PSEN2 (contigs 13) genes were identified. APP (contig 3 without translational error) was further analyzed using molecular modeling and docking to show its binding with curcumin (principal curcuminoid of turmeric) having -7.3 kcal/mol interaction energy for further consideration as a potential inhibitor.

SUBMITTER: Aathi M

PROVIDER: S-EPMC6900319 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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From EST to structure models for functional inference of APP, BACE1, PSEN1, PSEN2 genes.

Aathi Muthusankar M Piramanayagam Shanmughavel S

Bioinformation 20191031 10

Successive oxidative stress and biochemical changes results in neuronal death and neuritic plaques growth in Alzheimer's disease (AD). Therefore, it is interest to analyze amyloid-βeta precursor protein (APP), beta-secretase 1 (BACE1), presenilin (PSEN1 and PSEN2) genes from brain tissues to gain insights. Development of potential inhibitors for these targets is of significance. EST sequences of 2898 (APP), 539 (BACE1), 786 (PSEN1) and 314 (PSEN2) genes were analyzed in this study. A contig sequ ...[more]

PMID: 31831959

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Project description:BackgroundAlzheimer's disease (AD) mutations in amyloid precursor protein (APP) and presenilins (PSENs) could potentially lead to the production of longer amyloidogenic Aβ peptides. Amongst these, Aβ1-43 is more prone to aggregation and has higher toxic properties than the long-known Aβ1-42. However, a direct effect on Aβ1-43 in biomaterials of individuals carrying genetic mutations in the known AD genes is yet to be determined.MethodsN = 1431 AD patients (n = 280 early-onset (EO) and n = 1151 late-onset (LO) AD) and 809 control individuals were genetically screened for APP and PSENs. For the first time, Aβ1-43 levels were analysed in cerebrospinal fluid (CSF) of 38 individuals carrying pathogenic or unclear rare mutations or the common PSEN1 p.E318G variant and compared with Aβ1-42 and Aβ1-40 CSF levels. The soluble sAPPα and sAPPβ species were also measured for the first time in mutation carriers.ResultsA known pathogenic mutation was identified in 5.7% of EOAD patients (4.6% PSEN1, 1.07% APP) and in 0.3% of LOAD patients. Furthermore, 12 known variants with unclear pathogenicity and 11 novel were identified. Pathogenic and unclear mutation carriers showed a significant reduction in CSF Aβ1-43 levels compared to controls (p = 0.037; < 0.001). CSF Aβ1-43 levels positively correlated with CSF Aβ1-42 in both pathogenic and unclear carriers and controls (all p < 0.001). The p.E318G carriers showed reduced Aβ1-43 levels (p < 0.001), though genetic association with AD was not detected. sAPPα and sAPPβ CSF levels were significantly reduced in the group of unclear (p = 0.006; 0.005) and p.E318G carriers (p = 0.004; 0.039), suggesting their possible involvement in AD. Finally, using Aβ1-43 and Aβ1-42 levels, we could re-classify as "likely pathogenic" 3 of the unclear mutations.ConclusionThis is the first time that Aβ1-43 levels were analysed in CSF of AD patients with genetic mutations in the AD causal genes. The observed reduction of Aβ1-43 in APP and PSENs carriers highlights the pathogenic role of longer Aβ peptides in AD pathogenesis. Alterations in Aβ1-43 could prove useful in understanding the pathogenicity of unclear APP and PSENs variants, a critical step towards a more efficient genetic counselling.

Project description:BackgroundAmyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) mutations cause autosomal dominant forms of early-onset Alzheimer disease (AD-EOAD). Although these genes were identified in the 1990s, variant classification remains a challenge, highlighting the need to colligate mutations from large series.Methods and findingsWe report here a novel update (2012-2016) of the genetic screening of the large AD-EOAD series ascertained across 28 French hospitals from 1993 onwards, bringing the total number of families with identified mutations to n = 170. Families were included when at least two first-degree relatives suffered from early-onset Alzheimer disease (EOAD) with an age of onset (AOO) ≤65 y in two generations. Furthermore, we also screened 129 sporadic cases of Alzheimer disease with an AOO below age 51 (44% males, mean AOO = 45 ± 2 y). APP, PSEN1, or PSEN2 mutations were identified in 53 novel AD-EOAD families. Of the 129 sporadic cases screened, 17 carried a PSEN1 mutation and 1 carried an APP duplication (13%). Parental DNA was available for 10 sporadic mutation carriers, allowing us to show that the mutation had occurred de novo in each case. Thirteen mutations (12 in PSEN1 and 1 in PSEN2) identified either in familial or in sporadic cases were previously unreported. Of the 53 mutation carriers with available cerebrospinal fluid (CSF) biomarkers, 46 (87%) had all three CSF biomarkers-total tau protein (Tau), phospho-tau protein (P-Tau), and amyloid β (Aβ)42-in abnormal ranges. No mutation carrier had the three biomarkers in normal ranges. One limitation of this study is the absence of functional assessment of the possibly and probably pathogenic variants, which should help their classification.ConclusionsOur findings suggest that a nonnegligible fraction of PSEN1 mutations occurs de novo, which is of high importance for genetic counseling, as PSEN1 mutational screening is currently performed in familial cases only. Among the 90 distinct mutations found in the whole sample of families and isolated cases, definite pathogenicity is currently established for only 77%, emphasizing the need to pursue the effort to classify variants.

Project description:Alzheimer's disease is the most common neurodegenerative disease, characterized by dementia and premature death. Early-onset familial Alzheimer's disease is caused in part by pathogenic variants in presenilin 1 (PSEN1) and presenilin 2 (PSEN2), and alternative splicing of these two genes has been implicated in both familial and sporadic Alzheimer's disease. Here, we leveraged targeted isoform-sequencing to characterize thousands of complete PSEN1 and PSEN2 transcripts in the prefrontal cortex of individuals with sporadic Alzheimer's disease, familial Alzheimer's disease (carrying PSEN1 and PSEN2 variants), and controls. Our results reveal alternative splicing patterns of PSEN2 specific to sporadic Alzheimer's disease, including a human-specific cryptic exon present in intron 9 of PSEN2 as well as a 77 bp intron retention product before exon 6 that are both significantly elevated in sporadic Alzheimer's disease samples, alongside a significantly lower percentage of canonical full-length PSEN2 transcripts versus familial Alzheimer's disease samples and controls. Both alternatively spliced products are predicted to generate a prematurely truncated PSEN2 protein and were corroborated in an independent cerebellum RNA-sequencing dataset. In addition, our data in PSEN variant carriers is consistent with the hypothesis that PSEN1 and PSEN2 variants need to produce full-length but variant proteins to contribute to the onset of Alzheimer's disease, although intriguingly there were far fewer full-length transcripts carrying pathogenic alleles versus wild-type alleles in PSEN2 variant carriers. Finally, we identify frequent RNA editing at Alu elements present in an extended 3' untranslated region in PSEN2. Overall, this work expands the understanding of PSEN1 and PSEN2 variants in Alzheimer's disease, shows that transcript differences in PSEN2 may play a role in sporadic Alzheimer's disease, and suggests novel mechanisms of Alzheimer's disease pathogenesis.

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From EST to structure models for functional inference of APP, BACE1, PSEN1, PSEN2 genes.

Publications

From EST to structure models for functional inference of APP, BACE1, PSEN1, PSEN2 genes.

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