Johnny K. Ngsee
Johnny K. Ngsee
Pièce : Rm. 2442 RGN
Bureau : 613-562-5800 poste 2251
Courriel professionnel : firstname.lastname@example.org
Senior Scientist, Neuroscience, Ottawa Hospital Research Institute
Associate Professor, Department of Medicine and Cellular & Molecular Medicine, University of Ottawa
- Amyotrophic Lateral Sclerosis (ALS)
- Nuclear Pores
- Molecular Basis of Synaptic Transmission
- Vesicle Trafficking
- Protein Sorting
- Parkinson's disease
Mammalian cells are compartmentalized with proteins or enzymes localized to specific organelles. Newly synthesized proteins are processed and transported within the cell's secretory membrane compartments before final delivery to the proper cellular organelles. Disruption of some of these transport events is the molecular basis of many human hereditary and degenerative diseases. Research in my laboratory is focused on elucidating the molecular components of these protein sorting and vesicle trafficking machineries.
The endoplasmic reticulum (ER) is the first entry point to the secretory pathway for secretory and membrane proteins. The ER exerts a quality control role to ensure that only properly folded proteins are allowed to progress to the Golgi complex. Misfolded proteins are retrieved for refolding or destined for degradation. Properly folded proteins are sequentially moved from one membrane compartment to another by transport vesicles. They are loaded as cargoes into transport vesicles along with regulatory proteins that are required for their delivery to the intended target organelle. We have previously used a molecular approach to identify proteins that regulate these transport vesicles. We identified a novel protein which we named Prenylated Rab Acceptor (PRA). PRA recruits a class of molecular switches that control docking and fusion of transport vesicles with the target organelle called Rab GTPases to the membrane. We also identified a previously known protein, called VAMP-associated protein (VAP). We found that VAP regulates loading of protein cargoes into transport vesicles. There are two VAP genes in human encoding distinct proteins called VAPA and VAPB. Both are localized to the ER or membranes derived from the ER. Recently, a single amino acid substitution in VAPB is linked to a late-onset form of Amyotrophic Lateral Sclerosis (commonly referred to as Lou Gehrig's disease). Mutant VAPB forms insoluble aggregates that cause the ER to form large membrane structures (Fig. 1) and trap protein cargoes moving through the secretory pathway. Our research focuses on the molecular mechanisms by which mutant VAPB generates these VAPB-induced membrane structures, and their cellular consequences.
We recently found that expression of mutant VAPB also causes a nuclear envelope defect due to retention of nuclear envelope and pore proteins in the abnormal membrane structures generated by mutant VAPB. Our research found that VAPB function is required for final delivery of nuclear pore components to the nuclear envelope. This not only highlights a new mechanism by which proteins reach the nuclear envelope, but the progressive deterioration of nuclear pores in the absence of VAPB also provides a mechanism for the age-dependent onset of ALS. Nuclear pores are gatekeepers that regulate trafficking of molecules in and out of the nucleus. Damage or natural deterioration of pore components leads to loss of the nucleocytoplasmic permeability barrier (i.e. leaky pores), which is a hallmark of several age-dependent human diseases. This age dependence is partly due to the very long half-life of some pore proteins (some with a half-life of >1 year in rats). The second reason is synthesis of new pores occurs in a very narrow window – shortly after cell division. When a cell divides, the ~3,000 pores are evenly divided between the two daughter cells. Heightened pore synthesis occurs shortly after to double their number. Once reached, synthesis of new pores progressively decreases. Likewise, replacement of damaged pores is maintained at a very low level throughout interphase. Together, this renders non-dividing cells, such as neurons, more susceptible to age-dependent deterioration of the pores. Loss of VAPB function further reduces the cell's ability to make new pores or replace damaged pores, leading to enhance rate of deterioration. Our current research seeks to elucidate the molecular mechanism of mutant VAPB-induced disruption of transport to the nuclear envelope and to design reagents that can restore pore transport to the nuclear envelope.
synaptic vesicles, ALS