Biological Mechanism-based Neurology and Psychiatry: a BACE1/2 and Downstream Pathway Model

Abstract

: In Oncology, comprehensive Omics and functional enrichment studies led to an extensive profiling of (epi)genetic and neurobiological alterations that can be mapped onto a single tumor’s clinical phenotype and divergent clinical phenotypes expressing common pathophysiological pathways. Consequently, molecular pathway-based therapeutic interventions for different cancer typologies, namely tumor type- and site-agnostic treatments, have been developed, encouraging real-world implementation of a paradigm shift in medicine. Given the breakthrough nature of the new-generation translational research and drug development in Oncology, there is an increasing rationale to transfertilize this blueprint to other medical fields including Psychiatry and Neurology. To illustrate the emerging paradigm shift in neuroscience, we provide a state-of-the-art review of translational studies on the β-site amyloid precursor protein cleaving enzyme (BACE) and its most studied downstream effector, neuregulin, which are molecular orchestrators of distinct biological pathways involved in several neurological and psychiatric diseases. This body of data aligns with the evidence of a shared genetic/biological architecture among Alzheimer’s disease, schizoaffective and autism spectrum disorders. We engage in a speculative intellectual exercise gravitating around the BACE-related science, here used as paradigmatic case, to facilitating a forward-looking discussion about a potential first step towards the adoption of biological pathway-based, clinical symptom agnostic, categorization models in clinical Neurology and Psychiatry for precision medicine solutions. We draw a perspective whereby pathway-based therapeutic strategies could be catalyzed by high-throughput techniques, embedded in systems-scaled biology, neuroscience, and pharmacology approaches that will help overcome the constraints of traditional descriptive clinical symptom and syndrome-focused constructs in Neurology and Psychiatry.