Targeting Circuit Abnormalities in Neurodegenerative Disease

Despite significant improvement in our ability to diagnose both common and rare neurodegenerative diseases and understand their underlying biologic mechanisms, there remains a disproportionate lack of effective treatments, reflecting the complexity of these disorders. Successfully advancing novel treatments for neurodegenerative disorders will require reconsideration of traditional approaches, which to date have focused largely on specific disease proteins or cells of origin. This article proposes reframing these diseases as conditions of dysfunctional circuitry as a complement to ongoing efforts. Specifically reviewed is how aberrant spiking is a common downstream mechanism in numerous neurodegenerative diseases, often driven by dysfunction in specific ion channels. Surgical modification of this electrical activity via deep brain stimulation is already an approved modality for many of these disorders. Therefore, restoring proper electrical activity by targeting these channels pharmacologically represents a viable strategy for intervention, not only for symptomatic management but also as a potential disease-modifying therapy. Such an approach is likely to be a promising route to treating these devastating disorders, either as monotherapy or in conjunction with current drugs. SIGNIFICANCE STATEMENT: Despite extensive research and improved understanding of the biology driving neurodegenerative disease, there has not been a concomitant increase in approved therapies. Accordingly, it is time to shift our perspective and recognize these diseases also as disorders of circuitry to further yield novel drug targets and new interventions. An approach focused on treating dysfunctional circuitry has the potential to reduce or reverse patient symptoms and potentially modify disease course.