Special Issue on Disease: Mechanisms of Disease

With this issue of Neuron, we continue our series of special issues on neurological disease. This series highlights the efforts to understand the pathophysiology of disease, improve diagnosis, and ultimately alter clinical course. In the first installment of our series, we discussed various translational approaches to develop treatments for disorders of the nervous system. Understanding the mechanisms mediating disease is a crucial step toward finding cures, and in this issue, we present articles that evaluate the neural mechanisms underlying epilepsy, pain, neurodegeneration, and neurodevelopmental disorders. First, Jordan Stewart Farrell, Quynh-Anh Nguyen, and Ivan Soltesz review seizure mechanisms at the micro- and the macro-scale to advocate that both levels have to be examined and considered for a complete view of epilepsy and its effective treatment. In the previous special issue on translational approaches, Tracey et al. discussed the use of pain biomarkers for the effective treatment of pain. In the current issue, Ben Seymour illustrates that a reinforcement learning model of pain offers a mechanistic understanding of how the brain processes pain and supports its main function, which is the motivation to direct behavior away from harm. The next three articles discuss different aspects of the neural mechanisms underlying neurodegenerative diseases and their potential treatments. In his Perspective, Todd Golde explores the relationship between the immune system, brain proteinopathy, and neurodegenerative diseases. Golde argues that “immunoproteostasis” reflects multidirectional interactions between the immune system and the proteinopathies that are potential triggers of many neurodegenerative disorders. He then discusses the possibility of modulation of immunoproteostasis as a treatment option for neurodegenerative disease, particularly Alzheimer’s. Matthew M. McGregor and Alexandra B. Nelson comprehensively review the circuit mechanisms of Parkinson’s disease (PD). Specifically, the authors discuss the symptomatic and circuit aspects of many of the key clinical features of PD, including both motor and non-motor dysfunctions. In addition to the basal ganglia thalamocortical circuit central to PD, McGregor and Nelson also investigate PD-related changes in network activity. Next, Casey Cook and Leonard Petrucelli explore the cellular mechanisms underlying amyotrophic lateral sclerosis (ALS). Specifically, they focus on the pathogenic molecular consequences of repeat expansions in C9ORF72, which is the most common genetic cause of ALS, combined with the identification of new genetic mutations, to provide insight into the underlying mechanisms that cause ALS. As this article confirms, an accurate picture of the broad cell and molecular mechanisms underlying dysfunction is needed to develop a cure. Claudia Bagni and Suzanne Zukin review the synaptic mechanisms underlying two neurodevelopmental disorders, fragile X syndrome (FXS) and autism spectrum disorder (ASD). This broad article covers the aspects of FXS and ASD that intersect at the cell biological level, including the potential for overlapping molecular and/or cellular dysfunction at the synapse. In their NeuroView, Christine Fülling, Timothy G. Dinan, and John F. Cryan explore how gut microbiota can affect neural function and behavior. The authors argue that the vagus nerve plays a crucial role in the communication between the microbiota and the brain. The articles in this special issue show that while there is still much more to discover, we have made great progress in understanding the mechanisms mediating disease, from molecular events, such as protein aggregation and synaptic dysfunction, to behavioral alterations and complex circuit changes. The rapid pace at which these findings are evolving, and the many potential directions for future research, has the field poised to make powerful advances in our knowledge of disease. Stay tuned for our next special issue with a focus on psychiatric disease. This issue includes a broad range of insights, from mechanisms to developing treatments, that are transforming how we think about traditional psychiatric disorders.