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bioRxiv · 10.1101/2024.10.09.617477

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

Xu, J.·Duan, J.·Cai, Z.·Arai, C.·Di, C.·Venters, C. C.·Jones, M.·So, B.-R.·Dreyfuss, G.
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Abstract

The patho-mechanism of apolipoprotein variant, APOE4, the strongest genetic risk for late-onset Alzheimers disease (AD) and longevity, remains unclear. APOEs neighboring gene, TOMM40 (mitochondria protein transport channel), is associated with brain trauma outcome and aging-related cognitive decline, however its role in AD APOE4-independently is controversial. We report that TOMM40 is prone to transcription readthrough into APOE that can generate spliced TOMM40-APOE mRNA chimera (termed T9A2) detected in human neurons and other cells and tissues. T9A2 translation tethers APOE (normal APOE3 or APOE4) to near-full-length TOM40 that is targeted to mitochondria. Importantly, T9A2-APOE3 boosts mitochondrial bioenergetic capacity and decreases oxidative stress significantly more than T9A2-APOE4 and APOE3, and lacking in APOE4. We describe detailed interactomes of these actors that may inform about the activities and roles in pathogenesis. T9A2 uncovers a new candidate pathway for mitochondria regulation and oxidative stress-protection that are impaired in APOE4 genotypes and could initiate neurodegeneration.

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Xu, J., Duan, J., Cai, Z., Arai, C., Di, C., Venters, C. C., Jones, M., So, B.-R., Dreyfuss, G.. 2024-10-10. TOMM40-APOE chimera linking Alzheimer's highest risk genes: a new pathway for mitochondria regulation and APOE4 pathogenesis. https://doi.org/10.1101/2024.10.09.617477

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