DOI: 10.1101/497297Dec 15, 2018Paper

Imbalanced Nucleocytoskeletal Connections Create Common Polarity Defects in Progeria and Physiological Aging

BioRxiv : the Preprint Server for Biology
Wakam ChangGregg G Gundersen


Studies of the accelerated aging disorder Hutchinson-Gilford progeria syndrome (HGPS) can potentially reveal cellular defects associated with physiological aging. HGPS results from expression and abnormal nuclear envelope association of a farnesylated, truncated variant of prelamin A called progerin. We surveyed the diffusional mobilities of nuclear membrane proteins to identify proximal effects of progerin expression. The mobilities of three proteins were reduced in fibroblasts from children with HGPS compared to normal fibroblasts: SUN2, nesprin-2G, and emerin. These proteins function together in nuclear movement and centrosome orientation in fibroblasts polarizing for migration. Both processes were impaired in fibroblasts from children with HGPS and in NIH3T3 fibroblasts expressing progerin, but were restored by inhibiting protein farnesylation. Progerin affected both the coupling of the nucleus to actin cables and the oriented flow of the cables necessary for nuclear movement and centrosome orientation. Progerin overexpression increased levels of SUN1, which couples the nucleus to microtubules through nesprin-2G and dynein, and microtubule association with the nucleus. Reducing microtubule-nuclear connections through SUN1 d...Continue Reading

Related Concepts

Cell Nucleus
Dynein ATPase
Nuclear Envelope
Cell Polarity
Protein Farnesylation

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