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Luigi Puglielli

Luigi Puglielli

M.D., Ph.D., Catholic University of Rome (Italy)
Professor, Dept. of Medicine- Geriatrics
Wisconsin Alzheimer's Institute

Molecular mechanisms of neurodevelopment and neurodegeneration

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 N?-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.

Representative Publications
Peng, Y., Kim, M. J., Hullinger, R., O'Riordan, K. J., Burger, C., Pehar, M., & Puglielli, L. (2016). Improved proteostasis in the secretory pathway rescues Alzheimer's disease in the mouse. Brain, 139, 937-952.
View publication via DOI: DOI:10.1093/brain/awv385

Hoscheidt, S. M., Starks, E. J., Oh, J. M., Zetterberg, H., Blennow, K., Krause, R. A., ... Puglielli, L., Atwood, C. S., ... Asthana, S., Johnson, S. C., & Bendlin, B. B. (2016). Insulin resistance is associated with increased levels of cerebrospinal fluid biomarkers of Alzheimer's disease and reduced memory function in at-risk healthy middle-aged adults. Journal of Alzheimer's Disease, 52(4), 1373-1383.
View publication via DOI: DOI:10.3233/jad-160110

Li, M., Pehar, M., Liu, Y., Bhattacharyya, A., Zhang, S. C., O'Riordan, K. J., Burger, C., & Puglielli, L. (2015). The amyloid precursor protein (APP) intracellular domain regulates translation of p44, a short isoform of p53, through an IRES-dependent mechanism. Neurobiology of Aging, 36, 2725-2736.
View publication via DOI: DOI:10.1016/j.neurobiolaging.2015.06.021

Starks, E.J., O'Grady, P., Hoscheidt, S.M., Racine, A.M., Carlsson, C.M., Zetterberg, H., ... Okonkwo, O.C., Puglielli, L., Asthana, S., ... Anderson, R., ... Sager, M.A., Johnson, S.C., Bendlin, B.B. (2015). Insulin resistance is associated with higher cerebrospinal fluid tau levels in asymptomatic APOE Ε4 carriers. Journal of Alzheimer's Disease, 46(2), 525-33.
View publication via DOI: DOI:10.3233/JAD-150072

Ding, Y., Dellisanti, C.D., Ko, M.H., Czajkowski, C., & Puglielli, L. (2014). The ER-based acetyltransferases, ATase1 and ATase2, associate with the OST to acetylate correctly folded polypeptides. Journal of Biological Chemistry, 289(46), 32044-32055.
View publication via DOI: DOI:10.1074/jbc.M114.585547

Peng, Y., Li, M., Clarkson, B.D., Pehar, M., Lao, P.J., Hillmer, A.T., Barnhart, T.E., Christian, B.T., Mitchell, H.A., Bendlin, B.B., Sandor, M., & Puglielli, L. (2014). Deficient import of acetyl-CoA into the ER lumen causes neurodegeneration and propensity to infections, inflammation, and cancer. Journal of Neuroscience, 34(20), 6772-89.
View publication via DOI: DOI:10.1523/JNEUROSCI.0077-14.2014

Mak, A.B., Pehar, M., Nixon, A.M., Williams, R.A., Uetrecht, A.C., Puglielli, L., & Moffat, J. (2014). Post-translational regulation of CD133 by ATase1/ATase2-mediated lysine acetylation. Journal of Moecular Biology, 426(11), 2175-2182.
View publication via DOI: DOI:10.1016/j.jmb.2014.02.012

Mielke, M.M., Haughey, N.J., Bandaru, V.V., Zetterberg, H., Blennow, K., Andreasson, U., Johnson, S.C., Gleason, C.E., Blazel, H.M., Puglielli, L., Sager, M.A., Asthana, S., & Carlsson, C.M. (2014). Cerebrospinal fluid sphingolipids, beta-amyloid, and tau in adults at risk for Alzheimer's disease. Neurobiological Aging, 35(11), 2486-2494.
View publication via DOI: DOI:10.1016/j.neurobiolaging.2014.05.019

Pehar, M., & Puglielli, L. (2013). Lysine acetylation in the lumen of the er: A novel and essential function under the control of the upr. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1833(3), 686-697.
View publication via DOI: DOI:10.1016/j.bbamcr.2012.12.004

Pehar, M., Jonas, M. C., Hare, T. M., & Puglielli, L. (2013). SLC33A1/AT-1 regulates the induction of autophagy down-stream of IRE1/XBP1. Journal of Biological Chemistry, 287(35), 29921-29930.
View publication via DOI: DOI:10.1074/jbc.M112.363911

Sridharan, A., Pehar, M., Salamat, M. S., Pugh, T. D., Bendlin, B. B., Willette, A. A., Anderson, R. M., Kemnitz, J. W., . . . Weindruch, R., Puglielli, L., & Johnson, S. C. (2013). Calorie restriction attenuates astrogliosis but not amyloid plaque load in aged rhesus macaques: A preliminary quantitative imaging study. Brain Research, 1508, 1-8.
View publication via DOI: DOI:10.1016/j.brainres.2013.02.046

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.
View publication via DOI: DOI:10.1074/jbc.C112.362871

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.
View publication via DOI: DOI:10.1074/jbc.M111.310136

Bendlin, B.B., Carlsson, C.M., Johnson, S.C., Zetterberg, H., Blennow, K., Willette, A.A., Okonkwo, O. C., ... Puglielli, L., Asthana, S., & Sager, M.A. (2012). CSF t-tau/A 42 predicts white matter microstructure in healthy adults at risk for Alzheimer's disease. Public Library of Science One, 7(6), e37720.
View publication via DOI: DOI:10.1371/journal.pone.0037720

Pehar, M., Jonas, M.C., Hare, T., & Puglielli, L. (2012). SLC33A1/AT-1 regulates the induction of autophagy down-stream of IRE1/XBP1. Journal of Biological Chemistry, 287(35), 29921-29930.
View publication via DOI: DOI:10.1074/jbc.M112.363911

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.
View publication via DOI: DOI:10.1016/j.maturitas.2009.12.014

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.
View publication via DOI: DOI:10.1242/jcs.068841

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.
View publication via DOI: DOI:10.1111/j.1474-9726.2010.00547.x

Bendlin, B.B., Newman, L.M., Ries, M.L., Puglielli, L., Carlsson, C.M., Sager, M.A., ... Asthana, S., & Johnson, S.C. (2010). NSAIDs may protect against age-related brain atrophy. Frontiers in Aging Neuroscience, 2(35).
View publication via DOI: DOI:10.3389/fnagi.2010.00035

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.
View publication via DOI: DOI:10.1007/s12031-008-9088-0

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.
View publication via DOI: DOI:10.1074/jbc.M804901200

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.
View publication via DOI: DOI:10.1016/j.neurobiolaging.2007.01.010

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.
View publication via DOI: DOI:10.1038/embor.2008.132

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.
View publication via DOI: DOI:10.1016/j.neurobiolaging.2008.02.015

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.
View publication via DOI: DOI:10.1042/BJ20070040

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.
View publication via DOI: DOI:10.1074/jbc.M611426200

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.
View publication via DOI: DOI:10.1038/sj.emboj.7601062

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.
View publication via DOI: DOI:10.1042/BJ20050700

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.
View publication via DOI: DOI:10.1172/JCI23610C1

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.
View publication via DOI: DOI:10.1016/j.neuron.2004.08.043

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.
View publication via DOI: DOI:10.1385/JMN:24:1:093

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.
View publication via DOI: DOI:10.1074/jbc.M300466200

Puglielli, L., Tanzi, R.E., & Kovacs, D.M. (2003). Alzheimer's disease: the cholesterol connection. Nature Neuroscience, 6, 345-351.
View publication via DOI: DOI:10.1038/nn0403-345

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.
View publication via DOI: DOI:10.1038/ncb1001-905

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