mRNA-Binding Protein DJ-1 as a pivotal protein in AD pathology

BACKGROUND: Alzheimer'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. METHOD: Synaptically 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. RESULT: Synaptic 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. CONCLUSION: Decrease 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.