Instruct: Identify the main category of Biorxiv papers based on the titles and abstracts
Query: An alternatively spliced TREM2 isoform lacking the ligand binding domain is expressed in human brain BackgroundGenetic variants in TREM2 are strongly associated with Alzheimers Disease (AD) risk but alternative splicing in TREM2 transcripts has not been comprehensively described.

ObjectiveRecognizing that alternative splice variants can result in reduced gene expression and/or altered function, we sought to fully characterize splice variation in TREM2.

MethodsHuman blood and anterior cingulate autopsy tissue from 61 donors were used for end-point and quantitative PCR and Western blotting to identify and quantify novel TREM2 isoforms.

ResultsIn addition to previously described transcripts lacking exon 3 or exon 4, or retaining part of intron 3, we identified novel isoforms lacking exon 2, along with isoforms lacking multiple exons. Isoforms lacking exon 2 were predominant at approximately 10% of TREM2 mRNA in the brain. Expression of TREM2 and frequency of exon 2 skipping did not differ between AD samples and non-AD controls (p = 0.1268 and p = 0.4909, respectively). Further, these novel splice isoforms were also observed across multiple tissues with similar frequency (range 5.3 - 13.0%). We found that the exon 2 skipped isoform D2-TREM2 is translated to protein and localizes similarly to full-length TREM2 protein, that both proteins are primarily retained in the Golgi complex, and that D2-TREM2 is expressed in AD and non-AD brain.

ConclusionSince the TREM2 ligand binding domain is encoded by exon 2, and skipping this exon retains reading frame while conserving localization, we hypothesize that D2-TREM2 acts as an inhibitor of TREM2 and targeting TREM2 splicing may be a novel therapeutic pathway for AD.
24
The categories of this paper are: cancer
32
The categories of this paper are: zoology
16
The categories of this paper are: microbiology
10
The categories of this paper are: and
0
The categories of this paper are: genetics
14
The categories of this paper are: biophysics
25
The categories of this paper are: bioengineering
23
The categories of this paper are: immunology
19
The categories of this paper are: epidemiology
22
The categories of this paper are: physiology
28
The categories of this paper are: communication
27
The categories of this paper are: pathology
1
The categories of this paper are: bioinformatics
6
The categories of this paper are: plant
9
The categories of this paper are: synthetic
8
The categories of this paper are: genomics