(1) School of Biosciences, University of Nottingham, Nottingham, UK
(2) School of Medicine, University of Nottingham, Nottingham, UK
* Corresponding author Email: Andrew.email@example.com; Alexander.firstname.lastname@example.org
Control of protein manufacture at the point of translation is a crucial step in the regulation of gene expression and has shown to be important to many neurological processes, for example, synaptic plasticity and memory formation. The aim of this review was to discuss aberrant translation of proteins implicated in Alzheimer’s disease pathology.
Aberrant translation has been linked with neurodegenerative conditions such as Alzheimer’s disease; however, it is not fully understood how this aberrant protein synthesis occurs or how this may be sustained in Alzheimer’s disease. Cell stressors such as oxidative stress may enhance the translation of Alzheimer’s disease–associated proteins (e.g. amyloid precursor protein), and new research suggests that the cell survival response (e.g. elF2-alpha phosphorylation) may inadvertently up-regulate the translation of proteins such as BACE1; a process mediated in this instance by an upstream open reading frame located within the BACE1 5’UTR.
The research discussed in this review article has identified that in addition to regulation at the point of transcription and post-translational protein processing, the levels of proteins which negatively associate with Alzheimer’s disease pathology may also be controlled at the point of translation. Stressors such as oxidative stress may drive the transcription of amyloid precursor protein and the cleavage of amyloid precursor protein and may also enhance the translational efficiency of both amyloid precursor protein and the secretase responsible for cleaving amyloid precursor protein into its cytotoxic Abeta42 fragment. We suggest that selectively inhibiting the translation machinery in combination with reducing the levels of oxidative stress may represent a new therapeutic avenue for the treatment of Alzheimer’s disease.