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SRSF1 and PTBP1 Are trans-Acting Factors That Suppress the Formation of a CD33 Splicing Isoform Linked to Alzheimer's Disease Risk.
Mol Cell Biol. 2019 09 15; 39(18)MC

Abstract

A single nucleotide polymorphism (SNP) in exon 2 of the CD33 gene is associated with reduced susceptibility to late-onset Alzheimer's disease (AD) and causal for elevated mRNA lacking exon 2. In contrast to full-length CD33, transcripts lacking exon 2 result in CD33 protein unable to suppress activation responses in myeloid cells, including microglia. Currently, little is known about the regulation of CD33 exon 2 splicing. Using functional genomics and proteomic approaches, we found that SRSF1 and PTBP1 act as splicing enhancers to increase CD33 exon 2 inclusion in mRNA. Binding of PTBP1 to RNA sequences proximal to the intron 1-exon 2 splice junction is altered by the SNP and represents a potential mechanism behind the SNP-genotype dependent alternative splicing. Our studies also reveal that binding of SRSF1 to the CD33 RNA is not altered by the SNP genotype. Instead, a putative SRSF1 binding sequence at the 3' end of exon 2 directs CD33 exon 2 inclusion into the mRNA, indicating that PTBP1 and SRSF1 promote full-length isoform expression through different mechanisms. Our findings shed light on molecular interactions that regulate CD33 exon 2 splicing, ultimately impacting receptor expression on the cell surface. These data aid in the understanding of CD33's regulation of microglial signaling underpinning the AD genetic associations.

Authors+Show Affiliations

Internal Medicine Research Unit, Pfizer, Cambridge, Massachusetts, USA Petra.vanBergeijk@crl.com shasson@amgen.com. Computational Sciences, Pfizer, Cambridge, Massachusetts, USA.Chemical Biology and Medicine Design, Pfizer, Cambridge, Massachusetts, USA.Computational Sciences, Pfizer, Cambridge, Massachusetts, USA.Computational Sciences, Pfizer, Cambridge, Massachusetts, USA.Internal Medicine Research Unit, Pfizer, Cambridge, Massachusetts, USA Petra.vanBergeijk@crl.com shasson@amgen.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31208978

Citation

van Bergeijk, Petra, et al. "SRSF1 and PTBP1 Are trans-Acting Factors That Suppress the Formation of a CD33 Splicing Isoform Linked to Alzheimer's Disease Risk." Molecular and Cellular Biology, vol. 39, no. 18, 2019.
van Bergeijk P, Seneviratne U, Aparicio-Prat E, et al. SRSF1 and PTBP1 Are trans-Acting Factors That Suppress the Formation of a CD33 Splicing Isoform Linked to Alzheimer's Disease Risk. Mol Cell Biol. 2019;39(18).
van Bergeijk, P., Seneviratne, U., Aparicio-Prat, E., Stanton, R., & Hasson, S. A. (2019). SRSF1 and PTBP1 Are trans-Acting Factors That Suppress the Formation of a CD33 Splicing Isoform Linked to Alzheimer's Disease Risk. Molecular and Cellular Biology, 39(18). https://doi.org/10.1128/MCB.00568-18
van Bergeijk P, et al. SRSF1 and PTBP1 Are trans-Acting Factors That Suppress the Formation of a CD33 Splicing Isoform Linked to Alzheimer's Disease Risk. Mol Cell Biol. 2019 09 15;39(18) PubMed PMID: 31208978.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - SRSF1 and PTBP1 Are trans-Acting Factors That Suppress the Formation of a CD33 Splicing Isoform Linked to Alzheimer's Disease Risk. AU - van Bergeijk,Petra, AU - Seneviratne,Uthpala, AU - Aparicio-Prat,Estel, AU - Stanton,Robert, AU - Hasson,Samuel A, Y1 - 2019/08/27/ PY - 2018/12/15/received PY - 2019/06/08/accepted PY - 2019/6/19/pubmed PY - 2020/1/28/medline PY - 2019/6/19/entrez KW - Alzheimer’s disease KW - CD33 KW - antisense oligonucleotides KW - functional genomic screen KW - siRNA KW - splicing JF - Molecular and cellular biology JO - Mol. Cell. Biol. VL - 39 IS - 18 N2 - A single nucleotide polymorphism (SNP) in exon 2 of the CD33 gene is associated with reduced susceptibility to late-onset Alzheimer's disease (AD) and causal for elevated mRNA lacking exon 2. In contrast to full-length CD33, transcripts lacking exon 2 result in CD33 protein unable to suppress activation responses in myeloid cells, including microglia. Currently, little is known about the regulation of CD33 exon 2 splicing. Using functional genomics and proteomic approaches, we found that SRSF1 and PTBP1 act as splicing enhancers to increase CD33 exon 2 inclusion in mRNA. Binding of PTBP1 to RNA sequences proximal to the intron 1-exon 2 splice junction is altered by the SNP and represents a potential mechanism behind the SNP-genotype dependent alternative splicing. Our studies also reveal that binding of SRSF1 to the CD33 RNA is not altered by the SNP genotype. Instead, a putative SRSF1 binding sequence at the 3' end of exon 2 directs CD33 exon 2 inclusion into the mRNA, indicating that PTBP1 and SRSF1 promote full-length isoform expression through different mechanisms. Our findings shed light on molecular interactions that regulate CD33 exon 2 splicing, ultimately impacting receptor expression on the cell surface. These data aid in the understanding of CD33's regulation of microglial signaling underpinning the AD genetic associations. SN - 1098-5549 UR - https://www.unboundmedicine.com/medline/citation/31208978/SRSF1_and_PTBP1_Are_trans_Acting_Factors_That_Suppress_the_Formation_of_a_CD33_Splicing_Isoform_Linked_to_Alzheimer's_Disease_Risk_ L2 - http://mcb.asm.org/cgi/pmidlookup?view=long&pmid=31208978 DB - PRIME DP - Unbound Medicine ER -