Human APOER2 Isoforms Have Differential Cleavage Events and Synaptic Properties

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Alternative splicing generates protein diversity, particularly in the human brain.
• Human apolipoprotein E receptor 2 (APOER2) is a cell surface receptor involved in neuronal function.
• APOER2 undergoes proteolytic cleavage, releasing intracellular domains that regulate gene transcription.

Purpose of the Study:

• To identify and characterize human APOER2 splice variants in the cerebral cortex.
• To investigate how APOER2 isoform diversity affects proteolytic cleavage and synaptic function.
• To determine the functional consequences of specific APOER2 variants on neuronal activity.

Main Methods:

• Identification of APOER2 isoforms using gene-specific primers in human cerebral cortex.
• Analysis of APOER2 cleavage into C-terminal fragments (CTF) and intracellular domains (ICD) in response to APOE peptide.
• Functional assessment of APOER2 variants in mouse models using lentiviral gene delivery and electrophysiology.

Main Results:

• Twenty-five human APOER2 isoforms were identified, primarily involving exon skipping in ligand-binding regions.
• APOER2 isoforms with different ligand-binding repeat numbers showed varied CTF generation upon APOE stimulation.
• Loss of mouse Apoer2 reduced excitatory synapse activity; specific human APOER2 isoforms differentially restored this function.

Conclusions:

• Human APOER2 exhibits significant isoform diversity in the brain, impacting proteolytic processing.
• Differential cleavage and synaptic properties of APOER2 variants suggest distinct functional roles in neurons.
• APOER2 splice variants represent a mechanism for increasing proteomic complexity and regulating neuronal function in the human brain.