Dysregulated DJ1-Mediated Translation in Alzheimer's Disease

Abstract

Alzheimer’s Disease (AD) is a form of dementia with aberrant synaptic transmission. It has been hypothesized that disrupted calcium signaling may cause the digression from healthy memory to mild cognitive impairment (MCI) and eventually AD; and the search for the source of calcium dyshomeostasis continues still. The goal of this thesis is to take a bottom up approach to understanding the role of calcium in cellular memory during healthy and disease states. The mammalian target of rapamycin (mTOR) is a ubiquitously expressed kinase that governs protein synthesis, and is required for learning and memory. Here, we explore a downstream target of mTOR, the novel RNA-binding protein (RBP) Parkinson Protein 7 (DJ1) (Niere et al. 2016). Our data suggests, for the first time, that DJ1 is aberrantly expressed at the synaptic level in AD. Furthermore, a possible DJ1 target mRNA, CACNA2D2, is also aberrantly expressed at the synapses in AD, both at the mRNA and protein level. This work suggests that DJ1 may be a possible target upstream of L-type voltage-gated calcium channels (VGCC), and hence pose as a novel target for treatment of MCI, correcting calcium dynamics at the synapse.