S-nitrosylation-dependent pathological spread of abnormal proteins in frontotemporal dementia and lewy body dementia - aggregation and cell-to-cell spread of misfolded proteins are hallmarks of a…

S-nitrosylation-dependent pathological spread of abnormal proteins in frontotemporal dementia and lewy body dementia - aggregation and cell-to-cell spread of misfolded proteins are hallmarks of a variety of neurodegenerative diseases, leading to cellular dysfunction, synaptic damage, and neuronal loss. Cell-to-cell propagation of TDP- 43, α-synuclein (α-SYN), and TAU aggregates is thought to contribute to disease progression in alzheimer's disease (ad), lewy body dementia (LBD), frontotemporal dementia (FTD), and other neurodegenerative diseases. Moreover, mounting evidence suggests that these proteinopathies often CO-exist in the same patients to various degrees. Hence, understanding how these pathological proteins spread throughout the nervous system will open up new avenues for diagnostics and more effective therapeutics for these disorders. In patients with dementia, synaptic loss and neuronal damage result in part from excessive generation of reactive oxygen and nitrogen species (ROS/RNS) that is triggered by aggregated proteins. In fact, our group has extensively shown that misfolded protein-induced RNS, such as nitric oxide (no), contribute to synaptic damage in models of LBD, ad and FTD via aberrant protein s-nitrosylation (forming SNO-proteins). Intriguingly, we recently discovered that s-nitrosylation of TDP-43 and P62 promotes cell-to-cell transmission of TDP-43 and α-SYN, respectively. We have found that both TDP-43 and P62 are highly s-nitrosylated in human patient brains with dementia, as well as in hipsc (human induced pluripotent stem cell) and mouse models of FTD and LBD compared to controls. Concerning SNO-TDP-43, we found that s-nitrosylation contributes to aggregation of TDP-43 via oxidation-mediated disulfide-linkage; this process contributes to altered RNA- binding activity and neurotoxicity in both cell-based and transgenic mouse models of TDP-43 proteinopathy. Moreover, we found enhanced spreading of aggregated TDP-43 protein triggered by RNS-mediated oxidation, as seen in FTD. Concerning SNO-P62, we found that s-nitrosylation of the adaptor protein P62 inhibits autophagic flux, leading to intracellular build-up and consequent secretion of misfolded α-SYN via both direct release and secretion of extracellular vesicles. In the current application, we demonstrate redox-dependent spreading of abnormally aggregated proteins in hipsc models (2D cultures and 3D brain organoids) and mouse models of FTD and LBD. We use these models to show (i) seeding with s-nitrosylated/oxidized TDP-43 promotes TDP-43 spreading and TDP-43 proteinopathy, (II) SNO-P62 formation promotes α-SYN spreading and neurotoxicity, and (III) aberrant SNO-P62 and SNO-TDP-43 pathways interact to enhance TDP-43 and α-SYN spreading.