Remodeling without Destruction: Nonproteolytic Ubiquitin Chains in Neural Function and Brain Disorders

Ubiquitination is a fundamental posttranslational protein modification that regulates diverse biological processes, including those in the CNS. Several topologically and functionally distinct polyubiquitin chains can be assembled on protein substrates, modifying their fates. The classical and most prevalent polyubiquitin chains are those that tag a substrate to the proteasome for degradation, which has been established as a major mechanism driving neural circuit deconstruction and remodeling. In contrast, proteasome-independent nonproteolytic polyubiquitin chains regulate protein scaffolding, signaling complex formation, and kinase activation, and play essential roles in an array of signal transduction processes. Despite being a cornerstone in immune signaling and abundant in the mammalian brain, these nonproteolytic chains are under-appreciated in neurons and synapses in the brain. Emerging studies have begun to generate exciting insights about some fundamental roles played by these nondegradative chains in neuronal function and plasticity. In addition, their roles in a number of brain diseases are being recognized. In this article, we discuss recent advances on these non-conventional ubiquitin chains in neural development, function, plasticity and related pathologies.