Luigi Puglielli, MD, PhD

Portrait of Luigi Puglielli, MD, PhD
Associate Professor
Medicine
Address: 
D4247 VAH
2500 Overlook Terrace
Madison, WI 53792
Telephone: 
(608) 262-3287
Focus Groups: 
Neuroscience/Neuropathology
Education: 
MD, Catholic University, Rome, Italy
PhD, Catholic University, Rome, Italy
Research Summary: 
Molecular mechanisms of neurodevelopment and neurodegeneration
Research Detail: 

Our broad research interests are focused on molecular mechanisms of neurodevelopment and neurodegeneration. Our laboratory employs a combination of biochemical, cellular, molecular, and genetic approaches in in vitro, ex vivo and in vivo models. In 2007 we 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.

We now know that 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). We also know that 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. Our laboratory has generated mouse models that mimic the above diseases and dissected relevant pathogenic pathways. Our 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 include:

1) Dissection of biochemical and molecular pathways that link the ER acetylation machinery to neurodevelopmental and neurodegenerative diseases. Our group identified the ER acetylation machinery and showed its fundamental role in physiology and pathology. We are now expanding these study to clearly understand what “goes wrong” in associated human diseases. New relevant mouse models are being generated to extend our findings. Our 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. We now know that 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 us dissect specific pathogenic mechanisms and identify potential therapeutic targets.

3) Molecular mechanisms of cognitive loss during aging and Alzheimer’s disease neuropathology. We have 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. As mentioned above, 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. We have 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: 
Peng Y, Li M, Clarkson BD, Pehar M, Lao PJ, Hillmer AT, Barnhart TE, Christian BT, Mitchell HA, Bendlin BB, Sandor M, Puglielli L. (2014). Deficient import of acetyl-CoA into the ER lumen causes neurodegeneration and propensity to infections, inflammation, and cancer. J Neurosci 34: 6772-89.
Pehar M, Ko MH, Li M, Scrable H, Puglielli L. (2014). p44, the “longevity-assurance” isoform of p53, regulates tau phosphorylation and is activated in an age-dependent fashion. Aging Cell 13: 449-456.
Pehar, M., and Puglielli, L. (2013). Lysine acetylation in the lumen of the ER: a novel and essential function under the control of the UPR. Biochim Biophys Acta 1833:686-697.
Pehar M, Jonas MC, Hare T, Puglielli L. (2012). SLC33A1/AT-1 regulates the induction of autophagy down-stream of IRE1/XBP1. J Biol Chem 287:29921-29930.
Pehar, M., Lehnus, M., Karst, A., & Puglielli, L. (2012). Proteomic Assessment Shows That Many Endoplasmic Reticulum (ER)-resident Proteins Are Targeted by N-Lysine Acetylation in the Lumen of the Organelle and Predicts Broad Biological Impact. Journal of Biological Chemistry, 287(27), 22436-22440.
Ding, Y., Ko, M.H., Pehar, M., Kotch, F., Peters, N.R., Luo, Y., Salamat, S.M., & Puglielli, L. (2012). Biochemical inhibition of the acetyltransferases ATase1 and ATase2 reduces β-secretase (BACE1) levels and Aβ generation. Journal of Biological Chemistry 287(11), 8424-8433.
Bendlin, B.B., Carlsson, C.M., Gleason, C.E., Johnson, S.C., Sodhi, A., Gallagher, C.L., Puglielli, L., Engelman, C.D., Ries, M.L., Xu, G., Wharton, W., & Asthana, S. (2010). Midlife predictors of Alzheimer's disease. Maturitas, 65(2), 131-137.
Jonas, M.C., Pehar, M., & Puglielli, L. (2010). AT-1 is the ER membrane acetyl-CoA transporter and is essential for cell viability. Journal of Cell Science, 123(19), 3378-3388.
Pehar, M., O'Riordan, K.J., Burns-Cusato, M., Andrzejewski, M.E., del Alcazar, C.G., Burger, C., Scrable, H., & Puglielli, L. (2010). Altered longevity-assurance activity of p53:p44 in the mouse causes memory loss, neurodegeneration and premature death. Aging Cell, 9(2), 174-190.
Carlsson, C.M., Gleason, C.E., Puglielli, L., & Asthana, S. (2009). Dementia including Alzheimer’s disease. In J. Halter, J. Ouslander, M. Tinnetti, S. Studenski, & S. Asthana (Eds.), Hazzard’s Geriatric Medicine and Gerontology (6th ed.). New York: McGraw-Hill Professional.
Huttunen, H.J., Puglielli, L., Ellis, B.C., MacKenzie Ingano, L.A., & Kovacs, D.M. (2009). Novel N-terminal cleavage of APP precludes Aβ generation in ACAT-defective AC29 cells. J. Mol. Neurosci., 37(1), 6-15.
Ko, M.H., & Puglielli, L. (2009). Two ER/ERGIC-based lysine acetyltransferases post-translationally regulate BACE1 levels. Journal of Biological Chemistry, 284(4), 2482-2492.
Puglielli, L. (2008). Aging of the brain, neurotrophin signaling, and Alzheimer’s disease: is IGF1-R the common culprit? Neurobiology of Aging, 29(6), 795-811.
Jonas, M.C., Costantini, C., & Puglielli, L. (2008). PCSK9 is required for the disposal of non-acetylated intermediates of the nascent membrane protein BACE1. EMBO Rep., 9, 916-922.
Li, H., Costantini, C., Scrable, H., Weindruch, R., & Puglielli, L. (2008). Egr-1 and Hipk2 are required for the TrkA to p75NTR switch that occurs downstream of IGF1-R. Neurobiology of Aging, 30(12), 2010-2020.
Carlsson, C.M., Gleason, C.E., Hess, T.M., Moreland, K.A., Blazel, H.M., Koscik, R.L., Schreiber, N.T.N., Johnson, S.C., Atwood, C.S., Puglielli, L., Hermann, B.P., McBride, P.E., Stein, J.H., Sager, M.A., & Asthana, S. (2008). Effects of simvastatin on cerebrospinal fluid biomarkers and cognition in middle-aged adults at risk for Alzheimers disease. Journal of Alzheimers Disease, 13(2), 187-97.
Costantini, C., Ko, M.H., Jonas, M.C., & Puglielli, L. (2007). A reversible form of lysine acetylation in the ER and Golgi lumen controls the molecular stabilization of BACE1. Biochem. J., 407, 383-395.
Ko, M-H., & Puglielli, L. (2007). The sterol carrier protein SCP-x/pro-SCP-2 gene has transcriptional activity and regulates the Alzheimer’s disease g-secretase. Journal of Biological Chemistry, 282(27), 19742-19752.
Costantini, C., Scrable, H., & Puglielli, L. (2006). An aging pathway controls the TrkA to p75 neurotrophin receptor switch and amyloid beta-peptide generation in neurons. The European Molecular Biology Organization Journal, 25(9), 1997-2006.
Costantini, C., Kolasani, R.M.K., & Puglielli, L. (2005). Ceramide and cholesterol: possible connections between normal aging of the brain and Alzheimer’s disease. Just hypotheses or molecular pathways to be identified? Alzheimer’s & Dementia, 1, 43-50.
Costantini, C., Weindruch, R., Della Valle, G., & Puglielli, L. (2005). A TrkA to p75NTR molecular switch activates amyloid beta-peptide generation during aging. Biochemical Journal, 391, 59-67.
Puglielli, L., Friedlich, A.L., Setchell, K.D.R., Nagano, S., Opazo C., Cherny R.A., Barnham, K.J., Wade, J.D., Melov, S., Kovacs, D.M., & Bush, A.I. (2005). Alzheimer’s disease beta-amyloid activity mimics cholesterol oxidase. Journal of Clinical Investigation, 115(9), 2556-2563.
Hutter-Paier, B., Huttunen, H.J., Puglielli, L., Eckman, C.B., Kim, D.Y., Hofmeister, A., Moir, R.D., Dominitz, S.B., Frosch, M.P., Windisch, M., & Kovacs, D.M. (2004). The ACAT inhibitor CP-113,818 markedly reduces amyloid pathology in a mouse model of Alzheimer’s disease. Neuron, 44(2), 227-238.
Puglielli, L., Ellis, B.C., Ingano, L.A., & Kovacs, D.M. (2004). Role of acyl-coenzyme a: cholesterol acyltransferase activity in the processing of the amyloid precursor protein. J. Mol. Neurosci., 24, 93-96.
Puglielli, L., Ellis, B.C., Saunders, A.J., & Kovacs, D.M. (2003). Ceramide stabilizes BACE1 and promotes amyloid beta-peptide biogenesis. Journal of Biological Chemistry, 278(22), 19777-19783.
Puglielli, L., Tanzi, R.E., & Kovacs, D.M. (2003). Alzheimer’s disease: the cholesterol connection. Nature Neuroscience, 6, 345-351.
Puglielli, L., Konopka, G., Pack-Chung, E., MacKenzie Ingano, L.A., Berezovska, O., Hymam, B.T., Chang, T.Y., Tanzi, R.E., & Kovacs, D.M. (2001). Acyl coenzyme-A:cholesterol acyltransferase (ACAT) modulates the generation of the amyloid beta-peptide. Nature Cell Biology, 3, 905-912.