Quick Project Snapshot
Protein trafficking in neurodegenerative diseases.
Neurons under stress require rapid degradation or export of proteins that may be toxic. We have discovered that Ndfip1 is important for this process, for example, under conditions of metal poisoining, Ndfip1 directs degradation of the metal transporter DMT1 to seal off the entry of toxic metals. Under brain injury conditions, Ndfip1 is increased to mediate transport of proteins to promote neuron survival. Recently, we discovered that Ndfip1 is increased in degenerating neurons found in Parkinson's disease brain. In addition, Ndfip1 controls the abundance of proteins involved in the pathogenesis of Alzheimer's disease, such as APP and Fe65. In this project, we will examine more closely the molecular basis of this interaction, and use mouse disease models to interrogate this pathway. This project will use, knockout and transgenic mice, mouse models of disease and various biochemistry techniques.
- Howitt, J., Putz, U., Lackovic, J., Doan, A., Dorstyn, L., Cheng, H., Yang, B., Chan-Ling, T., Silke, J., Kumar, S. and Tan, S-S (2009). Divalent metal transporter 1 (DMT1) regulation by Ndfip1 prevents metal toxicity in human neurons. Proc. Natl. Acad. Sci. USA 106:15489-15494
- Howitt, J., Lackovic, J., Low, L-H., Naguib, A., Macintyre, A., Goh, C-P., Callaway, J.K., Hammond V., Thomas, T., Dixon, M., Putz, U. Silke, J., Bartlett, P., Yang, B., Kumar, S., Trotman, L.C., Tan, S-S. (2012). Ndfip1 regulates nuclear Pten import in vivo to promote neuronal survival following cerebral ischemia J. Cell Biol. 196:29-36
- Howitt, J., Gybers, A., Ayton, S., Carew-Jones, F., Putz, U., Finkelstein, D., Halliday, G., and Tan, S-S. (2014). Increased Ndfip1 in the substantia nigra of Parkinsonian brains is associated with elevated iron levels. Plos One 9(1):e87119.
Exosome Biology Laboratory
Brain cells are in constant communication with each other for transmitting electrical and chemical signals during mental activity. However, we believe that certain chemicals are also exchanged between brain cells for purposes that are not related to sensory and motor activity, for example for brain repair after injury. Brain communication is also important for protection of nerve cells against brain stress. We are currently engaged in discovering the nature of these communications and the circumstances behind their transmission.
We have been engaged in studying this natural method of communication using vesicles called exosomes. The exchanged material contains important messages (proteins, nucleic acids) that can have important consequences for cells that receive them. For example, in cancer, the spread of cancerous cells can be either hastened or retarded depending on the nature of these messages. Recently, we found out how to include certain additional messages that are normally not found in these exosomes. We are excited to study how these new messages can be used to repair brain cells after injury by boosting levels of repair proteins. In addition, we are enthusiastic about using these exosomes for transferring anti-cancer messages into brain tumours for reversing cancerous growth.
All Projects by this LabInvestigating interneuron migration and placement into cortical circuitsControl of protein transport in exosomes by Ndfip1How can Ndfip1 reduce brain damage following stroke?How does the brain protect itself during injury?Protein trafficking in neurodegenerative diseases.
Brain Development & Regeneration
Our group is interested in the self-defence mechanisms that operate in the brain when something goes wrong. This may take the form of degenerative disease (Parkinson's, Alzheimer's) or cancer (brain tumours) due to gene mutations and ageing. As a result, mutant or toxic proteins accumulate in brain cells, causing them to degenerate or proliferate. We have been working with one system of self-defence called protein ubiquitination which allows harmful proteins in brain cells to be removed and in the process, halt or reverse the disease process. We are particularly interested in finding how to accelerate beneficial ubiquitination in neurones using the Nedd4/Ndfip1 proteins. Our studies so far demonstrate that these proteins can halt cell death following injury and stroke, and slow down the division of brain cancer cells.