ABSTRACT
The covalent posttranslational modifications of proteins are critical events in signaling cascades that enable cells to efficiently, rapidly and reversibly respond to extracellular stimuli. This is especially important in the CNS where the processes affecting synaptic communication between neurons are highly complex and very tightly regulated. Sumoylation regulates the function and fate of a diverse array of proteins and participates in the complex cell signaling pathways required for cell survival. One of the most complex signaling pathways is synaptic transmission.Correct synaptic function is critical to the working of the brain and its alteration through synaptic plasticity mediates learning, mental disorders and stroke. The investigation of neuronal sumoylation is a new and exciting field and the functional and pathophysiological implications are far-reaching. Sumoylation has already been implicated in a diverse array of neurological disorders. Here we provide an overview of current literature highlighting recent insights into the role of sumoylation in neurodegeneration. In addition we present a brief assessment of drug discovery in the analogous ubiquitin system and extrapolate on the potential for development of novel therapies that might target SUMO-associated mechanisms of neurodegenerative disease.
Subject(s)
Nerve Degeneration , Neurodegenerative Diseases/metabolism , Neurons/metabolism , Signal Transduction , Small Ubiquitin-Related Modifier Proteins/metabolism , Sumoylation , Ubiquitin-Protein Ligases/metabolism , Animals , Humans , Neurodegenerative Diseases/drug therapy , Neurodegenerative Diseases/pathology , Neurodegenerative Diseases/physiopathology , Neurons/drug effects , Neurons/pathology , Neuroprotective Agents/therapeutic use , Signal Transduction/drug effects , Synaptic TransmissionABSTRACT
Small ubiquitin-related modifier (SUMO) proteins are approximately 11 kDa proteins that can be covalently conjugated to lysine residues in defined target proteins. The resultant post-translational modification, SUMOylation, is vital for the viability of mammalian cells and regulates, among other things, a range of essential nuclear processes. It has become increasingly apparent in recent years that SUMOylation also serves multiple functions outside the nucleus and that it plays a critical role in the regulation of neuronal integrity and synaptic function. In particular, dysfunction of the SUMOylation pathway has been implicated in the molecular and cellular dysfunction associated with neurodegenerative and psychiatric disorders. Here, we outline current knowledge of the SUMO pathway and discuss the growing evidence for its involvement in multiple neurodegenerative disorders, with a view to highlighting the potential of the SUMO pathway as a putative drug target.
