Cells (Jun 2021)

Proteogenomics Reveals Orthologous Alternatively Spliced Proteoforms in the Same Human and Mouse Brain Regions with Differential Abundance in an Alzheimer’s Disease Mouse Model

  • Esdras Matheus Gomes da Silva,
  • Letícia Graziela Costa Santos,
  • Flávia Santiago de Oliveira,
  • Flávia Cristina de Paula Freitas,
  • Vinícius da Silva Coutinho Parreira,
  • Hellen Geremias dos Santos,
  • Raphael Tavares,
  • Paulo Costa Carvalho,
  • Ana Gisele da Costa Neves-Ferreira,
  • Andrea Siqueira Haibara,
  • Patrícia Savio de Araujo-Souza,
  • Adriana Abalen Martins Dias,
  • Fabio Passetti

DOI
https://doi.org/10.3390/cells10071583
Journal volume & issue
Vol. 10, no. 7
p. 1583

Abstract

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Alternative splicing (AS) may increase the number of proteoforms produced by a gene. Alzheimer’s disease (AD) is a neurodegenerative disease with well-characterized AS proteoforms. In this study, we used a proteogenomics strategy to build a customized protein sequence database and identify orthologous AS proteoforms between humans and mice on publicly available shotgun proteomics (MS/MS) data of the corpus callosum (CC) and olfactory bulb (OB). Identical proteotypic peptides of six orthologous AS proteoforms were found in both species: PKM1 (gene PKM/Pkm), STXBP1a (gene STXBP1/Stxbp1), Isoform 3 (gene HNRNPK/Hnrnpk), LCRMP-1 (gene CRMP1/Crmp1), SP3 (gene CADM1/Cadm1), and PKCβII (gene PRKCB/Prkcb). These AS variants were also detected at the transcript level by publicly available RNA-Seq data and experimentally validated by RT-qPCR. Additionally, PKM1 and STXBP1a were detected at higher abundances in a publicly available MS/MS dataset of the AD mouse model APP/PS1 than its wild type. These data corroborate other reports, which suggest that PKM1 and STXBP1a AS proteoforms might play a role in amyloid-like aggregate formation. To the best of our knowledge, this report is the first to describe PKM1 and STXBP1a overexpression in the OB of an AD mouse model. We hope that our strategy may be of use in future human neurodegenerative studies using mouse models.

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