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TOMM40-APOE chimera linking Alzheimer's highest risk genes: a new pathway for mitochondria regulation and APOE4

Jinglei Xu, Jingqi Duan, Zhiqiang Cai

    Biorxiv : the Preprint Server for Biology
    |October 17, 2024
    PubMed

    Insights

    A novel gene chimera, T9A2, links TOMM40 and APOE variants to Alzheimer's disease risk. APOE3 variants improve mitochondrial function, while APOE4 variants show deficits, suggesting a new pathway in neurodegeneration.

    Area of Science:

    • Genetics
    • Neuroscience
    • Mitochondrial Biology

    Background:

    • The apolipoprotein E4 (APOE4) variant is the primary genetic risk factor for late-onset Alzheimer's disease (AD).
    • The role of the neighboring TOMM40 gene in AD, independent of APOE, is debated.
    • Understanding the interplay between TOMM40 and APOE is crucial for elucidating AD pathogenesis.

    Purpose of the Study:

    • To investigate the functional relationship between TOMM40 and APOE, particularly in the context of the APOE4 variant.
    • To identify novel molecular pathways contributing to AD risk and neurodegeneration.
    • To explore the impact of TOMM40-APOE chimeras on mitochondrial function and oxidative stress.

    Main Methods:

    • Analysis of transcription readthrough between TOMM40 and APOE genes.
    • Detection and characterization of spliced TOMM40-APOE mRNA chimeras (T9A2) in human cells and tissues.
    • Investigation of T9A2 translation products and their subcellular localization (mitochondria).
    • Assessment of mitochondrial bioenergetic capacity and oxidative stress levels in cells expressing different T9A2 variants.

    Main Results:

    • TOMM40 is prone to transcription readthrough, generating a T9A2 mRNA chimera found in human neurons and other tissues.
    • T9A2 translation results in APOE (APOE3 or APOE4) tethered to TOM40 and targeted to mitochondria.
    • T9A2-APOE3 significantly enhances mitochondrial bioenergetics and reduces oxidative stress compared to T9A2-APOE4 and standard APOE3.
    • APOE4 variants, in the context of T9A2, exhibit impaired mitochondrial function and increased oxidative stress.

    Conclusions:

    • The T9A2 chimera represents a newly identified pathway influencing mitochondrial regulation and oxidative stress protection.
    • Impaired mitochondrial function and oxidative stress protection associated with T9A2-APOE4 may initiate neurodegeneration in individuals with APOE4 genotypes.
    • This discovery offers potential therapeutic targets for mitigating AD risk in APOE4 carriers.

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