SUMOylation impact on synaptotoxicity of tau oligomers

Abstract

AbstractBackgroundTau oligomers (oTau) secreted by neurons and astrocytes are linked to the propagation of pathology and negatively affect neuronal activity and viability. oTau‐mediated synaptic loss leads to cognitive deficits and manifests the clinical outcomes of Alzheimer’s disease and related tauopathies. Small Ubiquitin‐like MOdifier (SUMO) proteins regulate multiple cellular events and SUMOylation plays pivotal roles in synaptic biology. Changes in SUMO conjugation and function are also linked to AD and related neurodegenerative disorders such as Huntington’s and Parkinson’s disease. The goal of this investigation is to determine the impact of the two main SUMO isoforms, SUMO1 and SUMO2, on oTau related synaptotoxicity.MethodSUMO1 and SUMO2 transgenic mice were generated with expression regulated by the neuron‐specific prion cos‐tet promoter. These in vivo models were used to generate double transgenic mice expressing human SUMO proteins and P301S mutant Tau. Changes in synaptic density and activity and the effects of oTau pathology were investigated with respect to cognitive deficits and long term potentiation (LTP).ResultElevated expression of human SUMO1 lead to impaired synaptic development and increased tau aggregation. SUMO1 transgenics crossed to Tau mutant mice resulted in an accelerated synaptic loss and a more severe disease phenotype as evidenced by LTP impairments and rapid cognitive decline. Conversely, SUMO2 conjugation levels were decreased in the presence of oTau and phospho‐tau pathology indicating a down‐regulation of its function. Enhanced SUMO2 expression in a mouse model of Tau pathology reversed this process and resulted in a significant reduction in oTau‐mediated synaptotoxicity and the associated LTP and cognitive impairments.ConclusionCumulatively, our findings indicate that SUMO1 negative impacts and exacerbates oTau‐related synaptic dysfunction. In contrast, SUMO2 confers substantial neuroprotection and represents a potential therapeutic avenue to counteract oTau‐induced synaptotoxicity in AD.