Browsing by Author "Westmark, Cara J."

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    FMRP Regulates the Nuclear Export of Adam9 and Psen1 mRNAs: Secondary Analysis of an N 6 -Methyladenosine Dataset
    (Nature Publishing group, 2020-07-01) Westmark, Cara J.; Maloney, Bryan; Alisch, Reid S.; Sokol, Deborah K.; Lahiri, Debomoy K.; Psychiatry, School of Medicine
    Fragile X mental retardation protein (FMRP) binds to and regulates the translation of amyloid-β protein precursor (App) mRNA, but the detailed mechanism remains to be determined. Differential methylation of App mRNA could underlie FMRP binding, message localization and translation efficiency. We sought to determine the role of FMRP and N6-methyladeonsine (m6A) on nuclear export of App mRNA. We utilized the m6A dataset by Hsu and colleagues to identify m6A sites in App mRNA and to determine if the abundance of message in the cytoplasm relative to the nucleus is altered in Fmr1 knockout mouse brain cortex. Given that processing of APP to Aβ and soluble APP alpha (sAPPα) contributes to disease phenotypes, we also investigated whether Fmr1KO associates with nuclear export of the mRNAs for APP protein processing enzymes, including β-site amyloid cleaving enzyme (Bace1), A disintegrin and metalloproteinases (Adams), and presenilins (Psen). Fmr1KO did not alter the nuclear/cytoplasmic abundance of App mRNA. Of 36 validated FMRP targets, 35 messages contained m6A peaks but only Agap2 mRNA was selectively enriched in Fmr1KO nucleus. The abundance of the APP processing enzymes Adam9 and Psen1 mRNA, which code for a minor alpha-secretase and gamma-secretase, respectively, were selectively enriched in wild type cytoplasm.
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    How autism and Alzheimer’s disease are TrAPPed
    (Springer Nature, 2021) Lahiri, Debomoy K.; Maloney, Bryan; Wang, Ruizhi; Sokol, Deborah K.; Rogers, Jack T.; Westmark, Cara J.; Psychiatry, School of Medicine
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    Novel Contribution of Secreted Amyloid-β Precursor Protein to White Matter Brain Enlargement in Autism Spectrum Disorder
    (Frontiers, 2019-04-10) Sokol, Deborah K.; Maloney, Bryan; Westmark, Cara J.; Lahiri, Debomoy K.; Neurology, School of Medicine
    The most replicated neuroanatomical finding in autism is the tendency toward brain overgrowth, especially in younger children. Research shows that both gray and white matter are enlarged. Proposed mechanisms underlying brain enlargement include abnormal inflammatory and neurotrophic signals that lead to excessive, aberrant dendritic connectivity via disrupted pruning and cell adhesion, and enlargement of white matter due to excessive gliogenesis and increased myelination. Amyloid-β protein precursor (βAPP) and its metabolites, more commonly associated with Alzheimer's disease (AD), are also dysregulated in autism plasma and brain tissue samples. This review highlights findings that demonstrate how one βAPP metabolite, secreted APPα, and the ADAM family α-secretases, may lead to increased brain matter, with emphasis on increased white matter as seen in autism. sAPPα and the ADAM family α-secretases contribute to the anabolic, non-amyloidogenic pathway, which is in contrast to the amyloid (catabolic) pathway known to contribute to Alzheimer disease. The non-amyloidogenic pathway could produce brain enlargement via genetic mechanisms affecting mRNA translation and polygenic factors that converge on molecular pathways (mitogen-activated protein kinase/MAPK and mechanistic target of rapamycin/mTOR), promoting neuroinflammation. A novel mechanism linking the non-amyloidogenic pathway to white matter enlargement is proposed: α-secretase and/or sAPPα, activated by ERK receptor signaling activates P13K/AKt/mTOR and then Rho GTPases favoring myelination via oligodendrocyte progenitor cell (OPC) activation of cofilin. Applying known pathways in AD to autism should allow further understanding and provide options for new drug targets.