Cytotoxic ApoE Cannot Reach Nucleus from Cytosol

Hence No Effect on Gene Expression, or Effect on Microtubules



Ronald B. DeMattos, Fayanne E. Thorngate, and David L. Williams (deceased) Department of Pharmacological Sciences, University Medical Center, State University of New York at Stony Brook, Stony Brook, New York 11794


Genetic evidence indicates that apolipoprotein E4 (apoE4) is a risk factor for the development of Alzheimer’s disease. A controversial hypothesis proposes that apoE, a typical secretory protein, accesses the neuronal cytosol in which apoE3, but not apoE4, protects tau from hyperphosphorylation. However, no conclusive evidence for the presence of apoE in the cytosolic compartment has been presented. We designed a novel assay to test whether apoE can access the cytosol via escape from the endocytic pathway by incorporating a nuclear localization signal (NLS) into apoE. Control experiments demonstrated that apoE plus NLS (apoE+NLS) is chaperoned to the nucleus if it reaches the cytosolic compartment. When exogenous apoE+NLS was endocytosed by neuronal cells, no nuclear apoE was detected, indicating that apoE remains within the endocytic pathway and does not escape into the cytosol. Furthermore, we show that direct cytosolic expression of apoE is cytotoxic. These data argue that effects of apoE on the neuronal cytoskeleton and on neurite outgrowth are not mediated via cytosolic interactions but rather by actions originating at the cell surface.



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