Find A PhysicianHome  |  Library  |  myDownstate  |  Newsroom  |  A-Z Guide  |  E-mail  |  Contact Us  |  Directions
curve gif

Lynette G. Sheffield, Ph.D.,

Research Assistant Professor

Department of Pathology

Office: BSB 4-27

Telephone: (718) 270-1220  Fax: (718) 270-3313

E-mail: lynette.sheffield@downstate.edu

 

 

 

The Role of the Nuclear Pore Complex and Nucleocytoplasmic Transport-Related Proteins in the Central Nervous System and Neurodegenerative Disorders

Bidirectional nucleocytoplasmic transport occurs through nuclear pore complexes (NPC) embedded in the nuclear envelope. The vertebrate NPC is a 60-125 MDa structure composed of approximately 30 distinct structural proteins (nucleoporins). Large macromolecules are actively transported through its central channel, while small molecules may diffuse through one of the eight channels in the symmetrical spoke-ring complex. One mechanism by which large proteins are transported into the nucleus is the following multistep process: A cytoplasmic protein containing a nuclear localization signal (NLS) is recognized and bound by one of the NPC-associated proteins, importin-a (karyopherin-a). This complex travels to the periphery of the nucleus where it is bound by another NPC-associated protein, importin-ß, and the entire complex is transported through the NPC into the nucleus. There are at least five forms of importin-a and several forms of importin-ß, indicating that specificity of nucleocytoplasmic transport may require selective binding of particular NLS.

In the central nervous system, the NPC and nucleocytoplasmic transport have not been extensively studied, and only recently have some of these proteins been linked to human disease. Conceivably, altered expression or function of the components of the NPC and/or nucleocytoplasmic transport may contribute to other disorders. Electron microscopic studies of “early” neurofibrillary tangle (NFT)-bearing neurons in Alzheimer’s disease (AD) brain biopsies revealed the proximity of paired helical filaments (PHF) to the nuclear envelope and NPC, NPC aggregation in adjacent neurons without apparent PHF, and striking nuclear irregularity in many tangle-bearing cells. We have found that NPC labeling consistently highlights the nuclear contour in all cell types in all cases, AD and control. Nuclear contour irregularity in neurons is significantly more common in AD than non-AD brains, occurring more frequently in neurons with NFT. However, we found no apparent difference in nucleoporin expression levels or distribution of several nucleoporins (Nup62, Nup88, Nup153, and Nup214).

Understanding of nucleocytoplasmic transport in the central nervous system is still developing. Our ongoing studies explore the expression, distribution and intracellular localization of NPC and nucleocytoplasmic transport-related proteins in human and rodent brain tissue, as well as primary cell culture.

Hippocampal neuron labeled for the nuclear pore complex protein Nup62 (red) and tau (green) in human brain. In this neurofibrillary tangle-filled neuron, the crease in the center of the nucleus indicates that the nucleus has folded in on itself, an irregular feature observed in Alzheimer’s disease. Hippocampal pyramidal neurons labeled for the nucleocytoplasmic transport protein importin ß (green) and dsDNA (ToPro3, red) in normal rat brain.

 

 

Recent Publications

1.  Sheffield, L.G., Miskiewicz, H.B., Tannenbaum, L.B., and Mirra, S.S. (2006) Nuclear pore complex proteins in Alzheimer disease. J. Neuropathol. Exp. Neurol., 65:45-54.

2.  John, J.E., Baptiste, S.L., Sheffield, L.G., von Gizycki, H., Kuzniecky, R.I., Devinsky, O., and Ludvig, N. (2007) Transmeningeal delivery of GABA to control neocortical seizures in rats. Epilepsy Res., 75:10-17.

3.  Ludvig, N., Sheffield, L.G., Tang, H.M., Baptiste, S.L., Devinsky, O., and Kuzniecky, R.I. (2008) Histological evidence for drug diffusion across the cerebral meninges into the underlying neocortex in rats. Brain Res., 1188:228-232.

 

Professional Society Memberships

Society for Neuroscience

American Society for Cell Biology

American Association for the Advancement of Science