ResearchTopic:
Mutant Ubiquitin Drives theEmergence
And Pathogenesis of Alzheimer’s Disease
Alzheimer’sdisease(AD) is characterized by accumulation of hazardous proteins in the brain. Asthe primary signal of protein clearance in the cell is ubiquitin, defectiveubiquitin signaling could play a pivotal role in the emergence of this disease.Although the only reported ubiquitin mutation, UBB+1,can be found in brains of all AD patients, mouse studies have failed insupplying a causal link with AD pathogenesis. By establishing a 3D neuronalnetwork utilizing human neuronal progenitors, we demonstrate that UBB+1expression alone can initiate the two pathological hallmarks of AD: Abplaques and neurofibrillary tangles.Specifically, we show that UBB+1competeswith ubiquitin for the binding to the neuroprotective enzyme UCH-L1 leading toelevated levels of Amyloid Precursor Protein and amyloid plaque buildup.Importantly, silencing UBB+1expressionis sufficient to hinder the emergence of AD hallmarks. Taken together, UBB+1plays a critical role in driving AD development, serving as a promisingtherapeutic target for the treatment of AD
