MRNA‐Binding Protein DJ‐1 as a pivotal protein in AD pathology

Abstract

AbstractBackgroundAlzheimer’s Disease (AD) is a complex neurodegenerative disorder of the synapse, characterized by the accumulation of amyloid beta plaques and neurofibrillary tangles. We have recently shown that Parkinson Protein 7, DJ‐1, is upregulated by mTORC1 activity, and is a translational hub that is predicted to coordinate the expression of a population of synaptic proteins (Niere et al., 2016). This cellular function of DJ‐1 is mediated through its RNA‐binding properties, yet many of its target mRNAs are unidentified, and the effects of this protein‐mRNA association are not well‐defined.MethodSynaptically increased DJ‐1 expression was determined by Western blotting of synaptoneurosomes from AD patients (Niere et al., 2020), and APP/PS1 and P301S mouse models of AD. DJ‐1 target mRNAs were first bioinformatically identified using a modified consensus sequence of DJ‐1 protein (van der Brug et al., 2008), and confirmed via RNA‐immunoprecipitation of DJ‐1 from WT mouse cortices. FMR1KO mouse cortices were used as a negative control.ResultSynaptic DJ‐1 expression is increased in a preclinical mouse model of AD exhibiting plaque pathology, and AD patients. Interestingly, there is no change in synaptic DJ‐1 levels in the P301S mouse model, which presents neurofibrillary tangles. We bioinformatically identified that mRNA coding for the RNA‐binding protein FMRP, and tau‐tubulin kinase 1 (TTBK1), known for phosphorylating pathogenic tau, as potential targets for DJ‐1, and confirmed it via RNA‐immunoprecipitation. Furthermore, the protein levels of FMRP is significantly decreased in the synapses of AD patients and APP/PS1 mice, while there is no change in the P301S model consistent with no change in DJ‐1 expression.ConclusionDecrease in FMRP in AD synapses where DJ‐1 expression is high suggests that DJ‐1 is a translational repressor of FMRP. FMRP binds to the mRNA of amyloid precursor protein (APP), the building block of amyloid beta plaques. Therefore, DJ‐1’s capacity to bind both Fmr1, coding for a protein which is known as a translational suppressor of APP mRNA (Borreca et al., 2016), and Ttbk1, a tau kinase involved in tau phosphorylation and aggregation (Sato et al., 2006) suggests that DJ‐1 might be at the crossroads of both AD hallmark pathologies.