The origin and impact of impaired ubiquitin signaling in the degeneration of neurons

Neurodegenerative diseases share similar hallmarks such as protein aggregation, suggesting that impaired protein degradation may be a common denominator. The major cellular pathways mediating protein degradation are the Ubiquitin-proteasome system (UPS) and autophagy, both regulated by ubiquitin signaling. However, aside from specific mutations in familial neurodegeneration cases, an early cause for failing ubiquitin-dependent proteolysis remains unclear. This proposal will test our unconventional hypothesis that dysregulated ubiquitin signaling is an early event in mechanisms of neurodegeneration, linking together numerous disease hallmarks. Towards this goal, we present groundbreaking findings that a mutated UPS protein resulting from a non-heritable transcription frameshift and present in the brains of neurodegenerative patients, particularly Alzheimer's disease (AD), is sufficient to trigger disease hallmarks in 3-D human neuronal cultures. This unique set-up replicates the main pathological hallmarks of AD without relying on any of the known genetic causes or risk factors. Utilizing this novel model, we have identified a previously unknown enzyme active site in a key neuroprotective protein, which now allows us to study the role of ubiquitin signaling in disease pathology.Specifically, this proposal seeks to understand both the source of disease-related ubiquitin signaling deterioration and its impact on neurons, by:1)Studying the mechanisms that trigger disruption of ubiquitin signaling in neurons.2)Understanding the consequences of altered ubiquitin signaling in human neuronal models of AD.3)Searching for mechanisms of neuroprotection mediated by key enzymes of the UPS. The outcome will develop new models of neurodegeneration, improve methods to study ubiquitin signaling in neurons, and yield a mechanistic understanding of UPS components in neuronal health and disease. Furthermore, the results will pave the way for developing new treatment approaches.