The following is a list of current projects taking place in the Puglielli lab.
Dissection of biochemical and molecular pathways that link the ER acetylation machinery to neurodevelopmental and neurodegenerative diseases.
- Our laboratory has developed several mouse models of dysfunctional ER acetylation. They all develop severe phenotypes that mimic associated human diseases.
- These models are being used to understand the pathophysiology of the diseases, dissect the metabolic pathways underlying the disease phenotypes, and identify biochemical and molecular regulators of the ER acetylation machinery.
Identification of the biochemical and molecular mechanisms that ensure the activity of the ER acetylation machinery and maintain intracellular cross-talk.
- Our studies in both cellular and animal models of dysfunctional ER acetylation have revealed the existence of biochemical and molecular events that ensure intracellular metabolic cross-talk and proteostasis within the ER and secretory pathway.
- Omic-and mechanistic-based strategies are being implemented to understand how the ER acetylation machinery regulates these fundamental events.
- Structural biochemistry is being used to understand essential aspects of the ER acetylation machinery.
Molecular mechanisms of cognitive loss during aging and Alzheimer’s disease neuropathology.
- Aging is the single most-important risk factor for late-onset Alzheimer’s disease. Mouse models of hyperactive ER acetylation develop a segmental form of progeria. Hyperactivity of the ER acetylation machinery is also observed as a function of normal aging and Alzheimer’s disease neuropathology.
- Ongoing studies are exploring possible new areas of overlap between brain aging and Alzheimer’s disease.
Drug discovery for the prevention and cure of neurodevelopmental and neurodegenerative disorders associated with dysfunctional ER acetylation.
- With a combination of High Throughput Screening, in silico modeling and biochemical approaches, we have identified ATase1 and ATase2 inhibitors.
- These inhibitors can rescue the progeria- and Alzheimer’s disease-like phenotypes in the mouse. Ongoing studies are exploring possible translational avenues.