Integrating Molecular Mechanisms with Synaptic Plasticity in Neurological Disease

Abstract

Brain disorders are among the most disturbing and challeng-ingpathologiesinourtime.Akeylessonreinforcedinthelasttwo decades is that the processes that contribute to neurolog-icaldiseasearenotexclusivetoeachdisorder;rather,thereareseveral common mechanisms. Recent studies have started todevelop amolecularframeworksupportingthe ideathatalter-ations in normal synaptic function are not only a core featurebut also a leading cause of disease. In this issue, MolecularNeurobiologydecidedtopublishasetofreviewssummarizingthe current state of knowledge on the molecular and synapticmechanisms of neurodegeneration that were discussed in arecentworkshopon“MetabolicRequirementsandChangesinCell Proliferation and Death” held in Calabria, Italy.One of the most challenging hypothesis explaining themolecular bases of neuronal apoptotic death in neurologicaldisorders is the notion that neurodegeneration may be anaberrant attempt of postmitotic neurons to acquire a mitoticphenotype and reenter the cell cycle. In this special issue ofMolecular Neurobiology, Almeida [1] revisits and providespotential mechanistic insights into the widely held notionthat postmitotic neurons cannot divide. She focuses anddescribes how the regulation of a cell cycle-related E3ubiquitin ligase—the anaphase promoting complex—keepsin check, by actively inducing protein destabilization, cyclinB1, and the glycolytic-promoting enzyme PFKFB3. Thisprocess strongly contributes to the typical neuronal postmi-totic phenotype and survival, hence supporting the idea thatnovel therapeutic strategies should also be focused on mod-ulating cell cycle-related targets. The above-mentioned lackof neuronal ability to divide may be overcome by replacingdamaged neurons or by restoring their function. Thus,Kittappa et al. [2] revisit the molecular mechanisms respon-sible for neuronal renewal from stem cells, which are pres-ent in specific niches within the adult brain. Furthermore,the authors bring the novel notion that even non-terminallydifferentiated neural stem cells play roles in the regenerationof neurons and their synaptic function by mechanisms be-yond mere cell replacement. These cells signal specificsurvival pathways that are worth investigating in our searchfor novel therapeutic strategies against neurodegeneration.According to this notion, noninvasive tools to follow-upsynaptic function in the living brain are, therefore, essentialfor our better understandingof neuronal regeneration.In thiscontext, Pilato et al. [3] discuss in detail the technical bases,as well as the clinical and experimental applications, ofthese new neurophysiological tools. The implementation ofthese techniques in routine research and clinical settings willnot only provide us with a follow-up of the functionalrecovery of neurons but also information about how to treatdrug-resistant neurological and psychiatric diseases.These articles therefore highlight the notion that synapseloss and synaptic dysfunction are critical parameters to beevaluated during the setting or progress of neurodegenerativediseases; among these, Alzheimer’s disease (AD) is the oneaffecting mostpeopleworldwide.Ingoodagreement withthehealth and social importance of this disorder, three of thereview articles of this special issue deal with different—butotherwise interconnected—aspects of the molecular mecha-nisms involved in AD. As Nistico et al. [4] pinpoints in thisspecial issue of Molecular Neurobiology, both synapse loss