Johnny K. Ngsee, PhD

jngsee@ohri.ca

That various mental disorders and neurodegenerative diseases result when brain cells malfunction seems almost too obvious to mention. Yet what makes the highly specialized brain cell tick is still essentially a mystery. Dr. Johnny Ngsee has undertaken to investigate the molecular mechanism that governs synaptic transmission. The fundamental activity of the brain is the process through which one neurone makes contact and signal to another through the release of a chemical called neurotransmitter. When a neurone fires, a microscopic bag called a synaptic vesicle fuses to the inside wall of the neurone's plasma membrane to release the neurotransmitter it contains to the exterior of the cell. This fusion process is also used by neurones to deliver proteins to the plasma membrane. Membrane proteins, such as ion channels that are crucial to transmission of the electrical impulse, are inserted into the membrane of the synaptic and other secretory vesicles shortly after they are made. They are incorporated into the plasma membrane when the synaptic vesicle fuses with the plasma membrane.

Dr. Ngsee studies the process of vesicle trafficking and how this might affect neuronal functions and survival. He examines the mechanisms by which a cell sort and deliver the vesicles to the correct target. In the brain, normal function as well as learning and memory involve maintenance and remodelling of synapses. This requires formation of new membrane structures with proper protein compositions from internal membrane stores. Membrane proteins and proteins destined to be released to the outside from the synapse must travel through an elaborate system of vesicular transport pathways inside the cell before reaching their final destination at the nerve endings. Complex regulatory mechanisms ensure that the cargo reaches the correct site, and disruption of these regulatory mechanisms not only result in delivery defect but also disrupt communications between neurones.

Of particular interest is his recent work on the relationship between vesicle trafficking and Amyotrophic Lateral Sclerosis (ALS). ALS, most commonly referred to as Lou Gehrig's disease, is a progressive neurodegenerative disease whereby motor neurones that innervate muscles die prematurely, resulting in paralysis. Approximately 90% of the cases of ALS are sporadic with the remaining inherited. There are currently 11 genes associated with the inherited form of ALS. Dr. Ngsee studies the ALS8 gene, which encodes a protein previously identified as vesicle-associated membrane protein (VAMP or Synaptobrevin)-associated membrane protein B (VAPB). A single amino acid mutation, proline at position 56 substituted by a serine (P56S), causes late-onset form of the disease. VAPB is a protein anchored to the membrane of the endoplasmic reticulum (ER), a network of membrane tubules inside the cell that is the entry point for most secretory and membrane proteins. The ER has a quality control feature to ensure proteins are correctly folded before they can leave the ER en route to their final destinations. Expression of VAPB-P56S disrupts this quality control feature and blocks the exit of proteins from the ER. This effectively creates a protein traffic jam that eventually leads to expansion of the ER and triggers a condition commonly referred to as ER stress. Cells counteract this ER stress by temporarily stopping new protein synthesis, by making more ER membranes, and by degrading the accumulated proteins. When these combined countermeasures fail to relieve the original stress, genes leading to cell death are then activated to eliminate the rogue cell. Dr. Ngsee has discovered that expression of a short peptide can change the activity of VAPB, and rescue the trafficking defect so that trapped proteins can now effectively leave the ER. Relieving the protein traffic jam effectively reduces ER stress and shuts down the cell's countermeasures. His current research focuses on why the expression of VAPB-P56S causes expansion of the ER in ALS8, the consequences of accumulation of expanded ER structures on the neurone, and the mechanisms by which this short peptide resolve or eliminate the expanded ER structures.