Luigi Puglielli

Veterans Administration Hosp

2500 Overlook Ter

Madison, WI 53705-2254

Education

• Catholic University of Rome (Rome, Italy) – MD and PhD
• Catholic University of Chile (Santiago, Chile) – Postdoctoral research fellow, Department of Gastroenterology
• Boston University – Research Associate, Department of Molecular and Cell Biology and Center for Advanced Biomedical Research

Professional Activities

Dr. Puglielli is a faculty member in the Division of Geriatrics and Gerontology in the Department of Medicine. Prior to joining the faculty at UW-Madison, he was an instructor in the Department of Neurology at Harvard Medical School and Massachusetts General Hospital. His research program focuses on molecular mechanisms of neurodevelopment and neurodegeneration. Honors bestowed upon Dr. Puglielli include being named as an Outstanding Scientist of the 21st century-International Biographical Center (Cambridge, UK), a National Academic Affairs – Excellence in Teaching award, a New Investigator Award from the UW School of Medicine and Public Health, the Puestow Award for sustained excellence in basic/translational science, and two Merit Awards from the Department of Veterans Affairs. He is a member of the Society for Neuroscience, American Society for Biochemistry and Molecular Biology, Federation of American Societies for Experimental Biology, the Royal Biochemical Society, and the Royal Chemical Society. Dr. Puglielli lectures in neurobiology, aging, and Alzheimer’s disease courses and seminars. He is a regular/permanent member of the National Institutes of Health Cellular Mechanisms in Aging and Development Study Section.

Research Interests

Dr. Puglielli’s research program focuses broadly on molecular mechanisms of neurodevelopment and neurodegeneration. His laboratory employs a combination of biochemical, cellular, molecular, and genetic approaches in in vitro, ex vivo and in vivo models. In 2007, his group reported that nascent proteins could undergo Nε-lysine acetylation in the lumen of the endoplasmic reticulum (ER). This discovery resulted in the identification of a previously unknown biochemical machinery that impacts on the biology of the ER.

The ER acetylation machinery regulates two essential functions of the ER: (i) efficiency of the secretory pathway (as part of quality control) and (ii) disposal of toxic protein aggregates that form within the secretory pathway (through autophagy). The flux of acetyl-CoA into the ER regulates cross-talk between different intracellular compartments. A dysfunctional ER acetylation machinery has been linked to developmental delay and premature death, autism spectrum disorder and intellectual disability, autosomal dominant spastic paraplegia-42, and Alzheimer’s disease. Dr. Puglielli’s laboratory has generated mouse models that mimic the above diseases and dissected relevant pathogenic pathways. These results support findings obtained from human-based studies and indicate that the ER acetylation machinery plays a crucial role in both neurodevelopmental and neurodegenerative diseases.

Active projects in the Puglielli laboratory include:

1. Dissection of biochemical and molecular pathways that link the ER acetylation machinery to neurodevelopmental and neurodegenerative diseases. The Puglielli group identified the ER acetylation machinery and showed its fundamental role in physiology and pathology. They are now expanding these studies to clearly understand what “goes wrong” in associated human diseases. New relevant mouse models are being generated to extend our findings. Their overall goal is to identify targets for possible therapeutic intervention.
2. Identification of the biochemical and molecular mechanisms that maintain cross-talk between different intracellular compartments. One fundamental aspect of cell biology is that the different intracellular compartments are able to talk to each other and maintain homeostasis. The intracellular flux of acetyl-CoA allows cross-talk between ER, cytosol, mitochondria, and nucleus. This “signaling function” of acetyl-CoA appears to be crucial for different forms of neurodevelopmental disorders (including autism spectrum disorder and intellectual disability, spastic paraplegia, neuronal hypoplasia and developmental delay, and epileptic encephalopathy) and neurodegenerative disorders (including Alzheimer’s disease and other forms of age-associated dementias). Therefore, it is imperative to identify the key players that regulate this intracellular cross-talk. This will help to dissect specific pathogenic mechanisms and identify potential therapeutic targets.
3. Molecular mechanisms of cognitive loss during aging and Alzheimer’s disease neuropathology. The Puglielli laboratory has identified a novel link between aging and Alzheimer’s disease, which, when hyperactive, results in synaptic and cognitive deficits, and in severe degeneration of memory-forming and -retrieving areas of the brain. The molecular mechanisms involved in these events are being actively sought.
4. Drug discovery for the prevention and cure of neurodevelopmental and neurodegenerative disorders associated with dysfunctional ER acetylation. The intracellular flux of acetyl-CoA and the ER acetylation machinery maintain the homeostatic balance of important cellular functions. This balance appears to be disrupted in specific neurodevelopmental and neurodegenerative disorders. The Puglielli laboratory has identified compounds that under certain conditions are able to reestablish the balance and correct associated deficits. Mechanisms of action as well as therapeutic potential are being actively studied.

Selected Publications

• Hullinger R, Li M, Wang J, Peng Y, Bomba E, Dowell J, Mitchell HA, Burger C, Chapman E, Denu J, Li L, Puglielli L. Increased influx of acetylCoA into the ER lumen causes autism spectrum disorder and mental retardation. J Exp Med 2016; 213: 1267-1284.
• Peng Y, Puglielli L. Nε-lysine acetylation in the lumen of the endoplasmic reticulum: a way to regulate autophagy and maintain protein homeostasis in the secretory pathway. Autophagy 2016; 12: 1051-1052.
• Peng Y, Kim MJ, Hullinger R, O’Riordan KJ, Burger C, Pehar M, Puglielli L. Improved proteostasis in the secretory pathway rescues Alzheimer’s disease in the mouse. Brain 2016; 139: 937-952.
• Li M, Pehar M, Liu Y, Bhattacharyya A, Zhang SC, O’Riordan KJ, Burger C, Puglielli L. The Amyloid Precursor Protein (APP) Intracellular Domain regulates translation of p44, a short isoform of p53, through an IRES-dependent mechanism. Neurobiol Aging 2015; 36: 2725-2736.
• Ding Y, Dellisanti CD, Ko MH, Czajkowski C, Puglielli L. The ER-based acetyltransferases, ATase1 and ATase2, associate with the OST to acetylate correctly folded polypeptides. J Biol Chem 2014; 289: 32044-32055.
• Peng Y, Li M, Clarkson BD, Pehar M, Lao PJ, Hillmer AT, Barnhart TE, Christian BT, Mitchell HA, Bendlin BB, Sandor M, Puglielli L. Deficient import of acetyl-CoA into the ER lumen causes neurodegeneration and propensity to infections, inflammation, and cancer. J Neurosci 2014; 34: 6772-89.
• Mak AB, Pehar M, Nixon AM, Williams RA, Uetrecht AC, Puglielli L, Moffat J. Post-translational regulation of CD133 by ATase1/ATase2-mediated lysine acetylation. J Mol Biol 2014; 426 :2175-2182.
• Pehar M, Ko MH, Li M, Scrable H, Puglielli L. p44, the “longevity-assurance” isoform of p53, regulates tau phosphorylation and is activated in an age-dependent fashion. Aging Cell 2014; 13: 449-456.
• Pehar M, Jonas MC, Hare T, Puglielli L. SLC33A1/AT-1 regulates the induction of autophagy down-stream of IRE1/XBP1. J Biol Chem 2012; 287: 29921-29930.
• Pehar M, Lehnus M, Karst A, Puglielli L. Proteomic assessment shows that many ER-resident proteins are targeted by Nε-lysine acetylation in the lumen of the organelle and predicts broad biological impact. J Biol Chem 2012; 287: 22436-22440.
• Ding Y, Ko MH, Pehar M, Kotch F, Peters NR, Luo Y, Salamat SM, and Puglielli L. Biochemical inhibition of the acetyltransferases ATase1 and ATase2 activity reduces β-secretase (BACE1) levels and Aβ generation. J Biol Chem 2012; 287: 8424-8433.
• Jonas, M.C., Pehar, M., and Puglielli, L. AT-1 is the ER membrane acetyl-CoA transporter and is essential for cell viability. J Cell Sci 2010; 123: 3378-3388.
• Pehar, M., O’Riordan, K.J., Burns-Cusato, M., Andrzejewski, M.E., del Alcazar, C.G., Burger, C., Scrable, H., and Puglielli, L. Altered longevity-assurance activity of p53:p44 in the mouse causes memory loss, neurodegeneration and premature death. Aging Cell 2010; 9:174-190.
• Ko, M.H., and L. Puglielli. Two ER/ERGIC-based lysine acetyltransferases post-translationally regulate BACE1 levels. J Biol Chem 2009; 284: 2482-2492.Jonas, M.C., C. Costantini, and L. Puglielli. PCSK9 is required for the disposal of non-acetylated intermediates of the nascent membrane protein BACE1. EMBO Rep 2008; 9: 916-922.
• Ko, M.-H. and L. Puglielli. The sterol carrier protein SCP-x/pro-SCP-2 gene has transcriptional activity and regulates the Alzheimer’s disease γ-secretase. J Biol Chem 2007; 282: 19742-19752.
• Costantini, C., H. Scrable, and L. Puglielli. An aging pathway controls the TrkA to p75 neurotrophin receptor switch and amyloid β-peptide generation in neurons. EMBO J 2006; 25: 1997-2006.
• Costantini, C., R. Weindruch, G. Della Valle, and L. Puglielli. 2005. A TrkA to p75NTR molecular switch activates amyloid β-peptide generation during aging. Biochem. J. 391: 59-67.