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

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1583
Author(s):  
Esdras Matheus Gomes da Silva ◽  
Letícia Graziela Costa Santos ◽  
Flávia Santiago de Oliveira ◽  
Flávia Cristina de Paula Freitas ◽  
Vinícius da Silva Coutinho Parreira ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Shotgun Proteomics ◽  
Transcript Level ◽  
Brain Regions ◽  
Rna Seq ◽  
Differential Abundance ◽  
Alternatively Spliced ◽  
Ad Mouse Model

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.

scholarly journals Expression of an alternatively spliced variant of SORL1 in neuronal dendrites is decreased in patients with Alzheimer’s disease

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Giulia Monti ◽  
Mads Kjolby ◽  
Anne Mette G. Jensen ◽  
Mariet Allen ◽  
Juliane Reiche ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Statistical Significance ◽  
Transcript Level ◽  
Brain Regions ◽  
Neuronal Dendrites ◽  
Lack Of Information ◽  
Synaptic Functions ◽  
Alternatively Spliced ◽  
Postmortem Brains

AbstractSORL1 is strongly associated with both sporadic and familial forms of Alzheimer’s disease (AD), but a lack of information about alternatively spliced transcripts currently limits our understanding of the role of SORL1 in AD. Here, we describe a SORL1 transcript (SORL1-38b) characterized by inclusion of a novel exon (E38b) that encodes a truncated protein. We identified E38b-containing transcripts in several brain regions, with the highest expression in the cerebellum and showed that SORL1-38b is largely located in neuronal dendrites, which is in contrast to the somatic distribution of transcripts encoding the full-length SORLA protein (SORL1-fl). SORL1-38b transcript levels were significantly reduced in AD cerebellum in three independent cohorts of postmortem brains, whereas no changes were observed for SORL1-fl. A trend of lower 38b transcript level in cerebellum was found for individuals carrying the risk variant at rs2282649 (known as SNP24), although not reaching statistical significance. These findings suggest synaptic functions for SORL1-38b in the brain, uncovering novel aspects of SORL1 that can be further explored in AD research.

REST/NRSF-induced changes of ChAT protein expression in the neocortex and hippocampus of the 3xTg-AD mouse model for Alzheimer's disease

Life Sciences ◽  
2014 ◽  
Vol 116 (2) ◽  
pp. 83-89 ◽  
Author(s):  
E. Orta-Salazar ◽  
A. Aguilar-Vázquez ◽  
H. Martínez-Coria ◽  
S. Luquín-De Anda ◽  
M. Rivera-Cervantes ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Protein Expression ◽  
Induced Changes ◽  
Ad Mouse Model

scholarly journals Altered slow (<1 Hz) and fast (beta and gamma) neocortical oscillations in the 3xTg-AD mouse model of Alzheimer's disease under anesthesia

2019 ◽  
Vol 79 ◽  
pp. 142-151 ◽  
Author(s):  
Patricia Castano-Prat ◽  
Lorena Perez-Mendez ◽  
Maria Perez-Zabalza ◽  
Coral Sanfeliu ◽  
Lydia Giménez-Llort ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Model Of Alzheimer’S Disease ◽  
Ad Mouse Model

RNA-Seq analysis of the parietal cortex in Alzheimer's disease reveals alternatively spliced isoforms related to lipid metabolism

2013 ◽  
Vol 536 ◽  
pp. 90-95 ◽  
Author(s):  
James D. Mills ◽  
Thomas Nalpathamkalam ◽  
Heidi I.L. Jacobs ◽  
Caroline Janitz ◽  
Daniele Merico ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Lipid Metabolism ◽  
Parietal Cortex ◽  
Rna Seq ◽  
Alternatively Spliced

scholarly journals Sex Differences in Healthspan Predict Lifespan in the 3xTg-AD Mouse Model of Alzheimer’s Disease

2018 ◽  
Vol 10 ◽  
Author(s):  
Alice E. Kane ◽  
Sooyoun Shin ◽  
Aimee A. Wong ◽  
Emre Fertan ◽  
Natalia S. Faustova ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Sex Differences ◽  
Mouse Model ◽  
Model Of Alzheimer’S Disease ◽  
Ad Mouse Model

scholarly journals Enhanced caffeine-induced Ca2+ release in the 3xTg-AD mouse model of Alzheimer's disease

2005 ◽  
Vol 94 (6) ◽  
pp. 1711-1718 ◽  
Author(s):  
Ian F. Smith ◽  
Brian Hitt ◽  
Kim N. Green ◽  
Salvatore Oddo ◽  
Frank M. LaFerla
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Model Of Alzheimer’S Disease ◽  
Ad Mouse Model

scholarly journals GSAP regulates mitochondrial function through the Mitochondria-associated ER membrane in the pathogenesis of Alzheimer’s disease

2020 ◽  
Author(s):  
Peng Xu ◽  
Jerry C. Chang ◽  
Xiaopu Zhou ◽  
Wei Wang ◽  
Michael Bamkole ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mitochondrial Function ◽  
Protein A ◽  
Transcript Level ◽  
Rna Seq ◽  
Single Nucleotide ◽  
Amyloidogenic Processing ◽  
App Trafficking ◽  
Lipid Environment

ABSTRACTBiochemical, pathogenic and human genetic data confirm that GSAP (γ-secretase activating protein), a selective γ-secretase modulatory protein, plays important roles in Alzheimer’s disease (AD) and Down syndrome. However, the molecular mechanism(s) underlying GSAP-dependent pathogenesis remains largely elusive. Here, through unbiased proteomics and single-nuclei RNA-seq, we identified that GSAP regulates multiple biological pathways, including protein phosphorylation, trafficking, lipid metabolism, and mitochondrial function. We demonstrated that GSAP physically interacts with Fe65:APP complex to regulate APP trafficking/partitioning. GSAP is enriched in the mitochondria-associated membrane (MAM) and regulates lipid homeostasis through the amyloidogenic processing of APP. GSAP deletion generates a lipid environment unfavorable for AD pathogenesis, leading to improved mitochondrial function and the rescue of cognitive deficits in an AD mouse model. Finally, we identified a novel GSAP single-nucleotide polymorphism that regulates its brain transcript level and is associated with an increased AD risk. Together, our findings indicate that GSAP impairs mitochondrial function through its MAM localization, and lowering GSAP expression reduces pathological effects associated with AD.

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