Nucleoskeleton-Cytoskeleton Connections and Cell Polarity in Aging

总结

SUMMARY The cytoskeleton and its connections to the nucleus play fundamental critical roles in establishing cellular morphology, polarity, migration and substrate adhesion. We have discovered a fundamental cell polarity defect that occurs in physiological aging and in children with the accelerated aging disorder Hutchinson-Gilford progeria syndrome. This defect results from imbalanced connections between the nuclear lamina on the inner aspect of the inner nuclear membrane and two major cytoskeletal protein systems: actin/microfilaments and microtubules. These connections are mediated by the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex composed of inner nuclear membrane SUN and outer nuclear membrane KASH proteins. In aging, there is a preferential interaction of increased SUN1 with microtubules versus SUN2 with actin/microfilaments. The parent funded grant (R01 AG064944) for this supplemental application is designed to test the hypothesis that altered nucleocytoskeletal connections mediated by the LINC complex cause an intrinsic cell polarity defect in aging. In this supplement, we will expand the parent project to examine nucleocytoskeletal connections in Alzheimer disease (AD) and related neurodegenerative dementias. The neuronal microtubule-associated protein tau accumulates in a hyperphosphorylated form in neurons in these disorders and amyloid-beta (Aβ) oligomers accumulate extracellularly and induce hyperphosphorylation of tau. We will therefore test the hypothesis that tau and oligomeric Aβ alter microtubule association with LINC complexes and interfere with the generation of cell polarity in a fibroblast model system and in primary neurons. In Aim 1, we will determine if tau and Aβ influence the interactions of microtubules with LINC complexes and alter the generation of cell polarity. To do so, we will use a robust fibroblast model system as proposed in the funded parent award. In Aim 2, we will determine if tau hyperphosphorylation induced by oligomeric Aβ oligomers increases microtubule interactions with the nucleus and perform experiments to establish if these altered interactions underlie concurrent pathological changes in primary neurons. Finally, we will also assess the effects of SUN1 overexpression, which occurs with aging, on primary neurons. This research will implicate tau/Aβ-induced dysfunction of the LINC complex in the pathogenesis of AD and related dementia, and potentially identify targets for the development of therapeutic treatments.