Nuclear Import Defects Drive Cell Cycle Dysregulation in Neurodegeneration

Abstract

Neurodegenerative diseases (NDDs) and other age-related disorders have been classically defined by a set of key pathological hallmarks. Two of these hallmarks, cell cycle dysregulation (CCD) and nucleocytoplasmic transport (NCT) defects, have long been debated as being either causal or consequential in the pathology of accelerated aging. Specifically, aberrant cell cycle activation in post-mitotic neurons has been shown to trigger neuronal cell death pathways and cellular senescence. Additionally, NCT has been observed to be progressively dysregulated during aging and in neurodegeneration, where the increased subcellular redistribution of nuclear proteins such as TAR DNA-Binding Protein-43 (TDP43) to the cytoplasm is a primary driver of many NDDs. However, the functional significance of NCT defects as either a primary driver or consequence of pathology, and how the redistribution of cell cycle machinery contributes to neurodegeneration, remains unclear. Here, we describe that pharmacological inhibition of importin-{beta} nuclear import is capable of perturbing cell cycle machinery both in mitotic neuronal cell lines and post-mitotic primary neurons in vitro. Our NemfR86S mouse model of motor neuron disease, characterized by nuclear import defects, further recapitulates the hallmarks of CCD in mitotic cell lines and in post-mitotic primary neurons in vitro, and in spinal motor neurons in vivo. The observed CCD is consistent with the transcriptional and phenotypical dysregulation observed in neuronal cell death and cellular senescence in NDDs. Together, this evidence suggests that impairment of nuclear import pathways resulting in CCD may be a common driver of pathology in neurodegeneration. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=106 SRC="FIGDIR/small/635269v1_figa1.gif" ALT="Figure 1"> View larger version (16K): org.highwire.dtl.DTLVardef@15a17d9org.highwire.dtl.DTLVardef@1d3af6eorg.highwire.dtl.DTLVardef@a291f5org.highwire.dtl.DTLVardef@11c9c5d_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract:C_FLOATNO Overview of Dysregulated Cell Cycle Mechanisms in Neuronal Cells. A nuclear import block drives cell cycle re-entry from G0, culminating in cell cycle arrest at G1/S. This cell cycle arrest is associated with activation of CKIs from the INK locus (p15, p16, p18, p19) and Cip/Kip (p21, p27) which act on specific CDK/Cyclin complexes. This activity is further associated with the G1/S downregulation E2F and stathmins, resulting in microtubule dysregulation and cell cycle arrest. C_FIG