Disrupted RNA‐networks in Alzheimer’s disease

Abstract

AbstractBackgroundSynapse loss is well‐documented and underlies cognitive decline in Alzheimer’s disease (AD) and other comorbid neuropsychiatric disorders such as depression. To date, few molecular targets and mechanisms are identified to restore/maintain healthy synapses in AD. AD and depression both have disrupted mechanistic/mammalian target of rapamycin complex 1 (mTORC1) activity. Since mTORC1 is involved in protein synthesis, disruptions in mTORC1 activity creates an imbalance between mRNA translation and repression at synapses. We have demonstrated that mTORC1 signaling is overactive in the prefrontal cortex (PFC) of AD patients and animal models. RNA binding proteins (RBP) are significant regulators of mRNA translation. A single RBP can bind to multiple mRNAs to either enhance or repress their translation. Dysregulated expression of RBPs can thus lead to imbalanced mRNA translation and protein synthesis.MethodComputational methods, combined with the literature, have identified putative DJ‐1 mRNA binding proteins. DJ‐1 RNA‐immunoprecipitation were used to verify FMR1 mRNA as a target. A new protein synthesis assay was used to test if DJ‐1 expression affects FMRP expression. Network analyses was performed to identify new targets shared and unique to these two RNA binding proteins.ResultWe recently identified the mTORC1 regulated RBP, DJ‐1 (Park7) as a translational regulator whose expression can impact the expression and/or function of multiple proteins. We have found that Fmr1 mRNA, which is translated to the RBP, fragile X messenger ribonucleoprotein 1 (FMRP), is a target of DJ‐1. We have shown that FMRP functions to suppress the translation of various synaptic mRNAs to maintain proper transsynaptic signaling which is essential in the formation, stability, and remodeling of synapses. Notably, depression is often comorbid with AD. Furthermore, we have demonstrated that FMRP is required for antidepressant efficacy. Herein, we provide data that supports disrupted DJ‐1/FMRP expression at the synapse in preclinical models of AD. Network analysis of how these two RNA binding proteins interact will be discussed and their impact on synapse stability and behaviors in AD.ConclusionDJ‐1 and FMRP RNA networks are disrupted in Alzheimer’s disease. Network analyses linking these two proteins may reveal novel targets involved in synapse stability and comorbid neuropsychiatric disorders.