Fig. 4

LSD1 is indispensable for neuronal health. a Loss of the neuronal-specific LSD1 isoform (LSD1n) reduces neurite length, branching, and width. LSD1n-specific null neurons are also hypoexcitable, and mice have a decreased susceptibility to seizures. Alternatively, loss of the entire LSD1 transcript in adult mice causes severe, rapid neurodegeneration as demonstrated by loss of neurites and pyknosis of affected nuclei. Cell death primarily occurs in the hippocampus and cortex. LSD1 mutant mice develop learning and memory deficits and die within 8 weeks post-deletion. b A model for LSD1 in Alzheimer’s disease emerges. As pathological hyperphosphorylated Tau tangles form in aging or sick neurons, LSD1 protein is sequestered in the cytoplasm, which inhibits its function as a histone demethylase. In the absence of nuclear LSD1, the complement cascade, microglial inflammatory response, and pluripotency-associated stem pathways become upregulated, while genes associated with ion transport and oxidative phosphorylation (OXPHOS) are downregulated. Though it is currently unclear which pathways are directly detrimental to cell health and which become perturbed as secondary effects, these aberrations cause neurons to die, leading to dementia in patients