Combs Lab
Lab Personnel
- Benjamin Combs, PhD, Principal Investigator
- Faheem Shejar, PhD, Research Associate
Overview
Misfolded and aggregated tau protein is a neuropathological hallmark of Alzheimer’s disease and other neurodegenerative disorders. In the diseased brain, these modified forms of tau can act as a driver of toxicity. Disease-related tau changes can include post-translational modifications like phosphorylation and truncation as well as inherited mutations within the tau gene itself. The Combs lab aims to identify how these modifications alter the normal function of tau and how they might cause toxicity and neurodegeneration. One of our main focuses is on understanding the role of tau protein in regulating fast axonal transport. Transport of material along the axon is critical for maintaining the health and function of the projection neurons that are vulnerable in disease. However, this process is disrupted in AD and many other neurodegenerative disorders. Multiple disease-related forms of tau disrupt normal fast axonal transport in various model systems including primary neurons cultures. This represents a possible mechanism for tau to induce toxicity in disease. With others we demonstrated that these disease modifications affect tau’s conformation and functional interactions with other proteins like protein phosphatase 1 resulting in changes to regulatory signaling pathways. We continue to study tau’s role in axonal transport to more fully understand how tau dysfunction leads to neurotoxicity and how tau’s novel role in affecting phosphorylation-based signaling pathways might affect other critical pathways. By doing this we hope to understand Alzheimer’s disease and related dementias on a molecular level to identify potential targets for therapeutic intervention.
There is a growing awareness that exposure to contaminants in the environment increases risk of developing Alzheimer’s disease and related dementias. The Combs lab uses multiple model systems (including rodents and C. elegans roundworms) to identify how exposure to specific toxins might affect the initiation and progression of tau-related dementias. One example is cadmium, a neurotoxic heavy metal that is linked to increased risk of dementia and death due to Alzheimer’s disease. Humans typically encounter increased levels of cadmium through smoking or eating contaminated food. We are examining how exposure to cadmium affects the initiation and progression of tau-related neuropathologies and related oxidative stress and neuroinflammation. This will allow us to identify potential synergistic mechanisms of neurotoxicity that could explain how exposure to cadmium increases disease risk. By understanding external factors that increase risk we can work to reduce those risks and prevent the disease before it starts.